1-216073261-C-T

Position:

chr1-216073261-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_206933.4(USH2A):c.5612G>A(p.Gly1871Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000266 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1871G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:3

Conservation

PhyloP100: 4.81

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:

USH2A-AS2 (HGNC:):

USH2A-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_206933.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0653944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.5612G>A	p.Gly1871Asp	missense_variant	28/72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A-AS2	NR_125992.1 linkuse as main transcript	n.136+661C>T		intron_variant
USH2A-AS2	NR_125993.1 linkuse as main transcript	n.136+661C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.5612G>A	p.Gly1871Asp	missense_variant	28/72	1	NM_206933.4	ENSP00000305941.3		O75445-1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

156

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000351

AC:

AN:

250594

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135440

show subpopulations

Gnomad AFR exome

AF:

0.00320

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.000795

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000186

AC:

272

AN:

1461626

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

127

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00275

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00111

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000899

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.00103

AC:

157

AN:

152158

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00291

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000246

Hom.:

Bravo

AF:

0.00124

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2023	Observed with a second USH2A variant (phase unknown) in a patient with retinitis pigmentosa and in an unrelated patient with hearing loss in published literature (Martin-Merida et al., 2019; Adeyemo et al., 2022); Observed in the heterozygous state with no other variant in the USH2A gene in a patient with retinitis pigmentosa in published literature; patient also harbored a variant in the EYS gene (Perez-Carro et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26806561, 30902645, 34837038, 34426522, 32483926) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2016	- -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 25, 2016	p.Gly1871Asp in exon 28 of USH2A: This variant is not expected to have clinical significance because it has been identified in 0.3% (36/10338) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140895792). -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2024	Variant summary: USH2A c.5612G>A (p.Gly1871Asp) results in a non-conservative amino acid change located in the Laminin G (IPR001791) and Fibronectin type III (IPR003961) domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 250594 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00035 vs 0.011), allowing no conclusion about variant significance. c.5612G>A has been reported in the literature in individuals affected with hearing loss and retinitis pigmentosa (examples: Perez-Carro_2015, Martin-Merida_2019, Adeyemo_2022). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34837038, 33623043, 30902645, 26806561). ClinVar contains an entry for this variant (Variation ID: 48537). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Retinitis pigmentosa 39

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

DBGen Ocular Genomics

Jun 23, 2021

- -

Childhood onset hearing loss

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

National Institute on Deafness and Communication Disorders, National Institutes of Health

Jul 08, 2021

PP3 (non REVEL) / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging. -

Usher syndrome type 2A

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.065

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

3.0

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.66

Sift

Uncertain

0.010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.76

MVP

0.94

MPC

0.26

ClinPred

0.091

GERP RS

5.9

Varity_R

0.49

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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