rs780779563

Variant summary

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

The NM_206933.4(USH2A):​c.545_546delAA​(p.Lys182ArgfsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K182K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

USH2A
NM_206933.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.83
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-216418618-CTT-C is Pathogenic according to our data. Variant chr1-216418618-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 556324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216418618-CTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
USH2ANM_206933.4 linkc.545_546delAA p.Lys182ArgfsTer33 frameshift_variant Exon 3 of 72 ENST00000307340.8 NP_996816.3 O75445-1
USH2ANM_007123.6 linkc.545_546delAA p.Lys182ArgfsTer33 frameshift_variant Exon 3 of 21 NP_009054.6 O75445-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.545_546delAA p.Lys182ArgfsTer33 frameshift_variant Exon 3 of 72 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000366942.3 linkc.545_546delAA p.Lys182ArgfsTer33 frameshift_variant Exon 3 of 21 1 ENSP00000355909.3 O75445-2
USH2AENST00000674083.1 linkc.545_546delAA p.Lys182ArgfsTer33 frameshift_variant Exon 3 of 73 ENSP00000501296.1 O75445-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250896
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135594
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:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461098
Hom.:
0
AF XY:
0.00000275
AC XY:
2
AN XY:
726850
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Nov 02, 2018
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.545_546delAA variant in the USH2A gene has been reported previously in association with autosomal recessive Usher syndrome type II (Sayedahmadi et al., 2004; Hartel et al., 2016). In addition, the c.545_546delAA variant has been reported in an individual with retinitis pigmentosa who also had another frameshift variant in the USH2A gene (Sandberg et al., 2008). The c.545_546delAA variant causes a frameshift starting with codon Lysine 182, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 33 of the new reading frame, denoted p.Lys182ArgfsX33. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.545_546delAA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.545_546delAA as a pathogenic variant. -

Mar 09, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys182Argfs*33) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Usher syndrome type II (PMID: 15325563, 18273898, 27318125). ClinVar contains an entry for this variant (Variation ID: 556324). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 39 Pathogenic:2
Nov 21, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 04, 2023
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Usher syndrome type 2A Pathogenic:2
Aug 23, 2021
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 04, 2023
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
Jan 24, 2018
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:1
Aug 07, 2018
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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.

Other links and lift over

dbSNP: rs780779563; hg19: chr1-216591960; API