chr1-216289412-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_206933.4(USH2A):c.1841-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000211 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

USH2A
NM_206933.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 6.89

Variant links:

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

USH2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.9, offset of -50, new splice context is: tttaattttgaattatgcAGctg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-216289412-T-C is Pathogenic according to our data. Variant chr1-216289412-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 48476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216289412-T-C is described in Lovd as [Pathogenic]. Variant chr1-216289412-T-C is described in Lovd as [Likely_pathogenic]. Variant chr1-216289412-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.1841-2A>G		splice_acceptor_variant, intron_variant	Intron 10 of 71	ENST00000307340.8	NP_996816.3	O75445-1
USH2A	NM_007123.6 link	c.1841-2A>G		splice_acceptor_variant, intron_variant	Intron 10 of 20		NP_009054.6	O75445-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
USH2A	ENST00000307340.8 link	c.1841-2A>G	splice_acceptor_variant, intron_variant	Intron 10 of 71	1	NM_206933.4	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3 link	c.1841-2A>G	splice_acceptor_variant, intron_variant	Intron 10 of 20	1		ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1 link	c.1841-2A>G	splice_acceptor_variant, intron_variant	Intron 10 of 72			ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251270

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461520

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Usher syndrome type 2A

Pathogenic:4

Sep 22, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 39 (MIM#613809), and Usher syndrome, type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been proven to cause skipping of exon 11 leading to a frameshift and a premature termination codon. The predicted outcome is nonsense-mediated decay (NMD) (PMID: 20497194). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in mostly homozygous or compound heterozygous individuals with Usher syndrome, and less commonly compound heterozygous individuals with retinitis pigmentosa (ClinVar, PMID: 12525556, 20497194, 22004887, 24875298). (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (c.5298+5G>A) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2021

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_206933.2(USH2A):c.1841-2A>G is a canonical splice variant classified as pathogenic in the context of USH2A-related disorders. c.1841-2A>G has been observed in cases with relevant disease (PMID: 12525556, 19683999, 31231422, 22004887, 32036094, 32531858, 28157192, 22135276, 24944099, 28559085, 27596865, 25575603). Functional assessments of this variant are available in the literature (PMID: 20497194). c.1841-2A>G has been observed in population frequency databases (gnomAD: NFE 0.004%). In summary, NM_206933.2(USH2A):c.1841-2A>G is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

not provided

Pathogenic:3

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 10 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs397518003, gnomAD 0.004%). Disruption of this splice site has been observed in individuals with USH2A-related conditions (PMID: 12525556, 27460420, 29986705). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS10-2A>G. ClinVar contains an entry for this variant (Variation ID: 48476). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20497194). For these reasons, this variant has been classified as Pathogenic. -

Oct 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a second USH2A variant in many patients with Usher syndrome or hearing loss in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Sandberg et al., 2008; Vozzi et al., 2011; Zhang et al., 2016; Bonnet et al., 2016; Cabanillas et al., 2018); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33576794, 31589614, 32037395, 32036094, 31736247, 24875298, 27596865, 15823922, 19683999, 18641288, 21738395, 29986705, 31231422, 28559085, 24944099, 21569298, 22135276, 21487335, 27460420, 12525556, 25525159, 22004887, 20497194) -

Retinitis pigmentosa 39

Pathogenic:3

Mar 21, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The USH2A c.1841-2A>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PS3, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Jul 15, 2021

INGEBI, INGEBI / CONICET

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.1841-2 A>G variant in USH2A gene has benn found in 4/113596 alleles only in european non-finnish population (0.0012% with 95% CI) meeting PM2 rule . This type of variant is predicted to generate a lost of the acceptor splicing site in USH2A gene , which is a known mechanism of disease, PVS1. The c.1841-2 A>G has been identified in trans with different pathogenic variants in at least 10 individuals (PM3_VS): 2 patients with retinitis pigmentosa, 9 cases of type 2 Usher patients (PP4), one type 3 Usher patient and 3 hearing loss patients (variants detected in early childhood); (PMID:12525556, 18641288, 19683999, 21738395, 22004887, 22135276, 24875298, 24944099, 25558175, 25575603, 29986705, 27460420, this report). The c.1841-2 A>G segregated correctly in two familial cases: one family composed of two siblings with retinitis pigmentosa and two unaffected siblings and a second familiy case composed of two siblings with hearing loss (PMID: 12525556, 24875298) applying to PP1_Mod. Functional studies in COS-7 cells using minigen system demonstrated that this variant generated the skippining of exon 11 leading to a freamshift: p.Gly614Aspfs6* (PMID20497194); PS3_Supp.Considering PM2, PVS1_VS, PP4, PP1_M, PS3_S the variant is classfied as Pathogenic for Usher Syndrome and retinitis pigmentosa. -

Rare genetic deafness

Pathogenic:1

Dec 04, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1841-2A>G variant in USH2A has been reported in at least 12 probands with Usher syndrome and 2 probands with retinitis pigmentosa (RP), including at least 3 homozygous individuals and 7 individuals who were compound heterozygous for a second pathogenic USH2A variant (Bernal 2003, Maubaret 2005, Sandberg 2008, Jai jo 2010, Garcia-Garcia 2011, Vozzi 2011, LeQuesne Stabej 2012, Sodi 2014, Lenard uzzi 2015, Bonnet 2016, LMM data). This variant segregated with RP in one affect ed sibling (Bernal 2003). It has also been identified in 0.003% (4/113596) of Eu ropean chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this f requency is low enough to be consistent with a recessive carrier frequency. Fina lly, the c.1841-2A>G variant is located in the canonical splice consensus sequen ce and functional studies demonstrate that it causes skipping of exon 11, leadin g to a frameshift and the introduction of a premature termination codon (Jaijo 2 011). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP criteria applied: PVS1, PM3_VerySt rong, PM2, PP4. -

USH2A-related disorder

Pathogenic:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The USH2A c.1841-2A>G occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1841-2A>G variant has been reported in ten studies in which it is found in a total of 14 individuals including five homozygotes, two compound heterozygotes and five heterozygotes with Usher syndrome, and two compound heterozygotes with autosomal recessive retinitis pigmentosa (Bernal et al. 2003; Maubaret et al. 2005; Sandberg et al. 2008; Jaijo et al. 2010; Jaijo et al. 2011; Garcia-Garcia et al. 2011; Vozzi et al. 2011; Le Quesne Stabej et al. 2012; Baux et al. 2014). The variant was also observed in a homozygous state in two siblings with non-syndromic hearing loss in whom no visual phenotype was reported (Vona et al. 2014). The variant was shown to co-segregate with autosomal recessive retinitis pigmentosa in one family (Bernal et al. 2003; Sandberg et al. 2008). The c.1841-2A>G variant was absent from 1272 control chromosomes and is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Using minigene assays the c.1841-2A>G variant was shown to cause skipping of exon 11 and an r.1841_1971del change at the RNA level, leading to a frameshift (p.Gly614AspfsX6) with premature truncation and the loss of approximately 88% of the protein. Based on the collective evidence and potential impact of splice acceptor variants, the c.1841-2A>G variant is classified as pathogenic for USH2A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.98

GERP RS

5.4

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: -6

DS_AL_spliceai

0.99

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over