rs587776538

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_206933.4(USH2A):​c.240_241insGATC​(p.Gln81fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T80T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

USH2A
NM_206933.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:3

Conservation

PhyloP100: 1.26
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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 1-216422096-G-GGATC is Pathogenic according to our data. Variant chr1-216422096-G-GGATC is described in ClinVar as [Pathogenic]. Clinvar id is 2360.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USH2ANM_206933.4 linkc.240_241insGATC p.Gln81fs frameshift_variant 2/72 ENST00000307340.8 NP_996816.3 O75445-1
USH2ANM_007123.6 linkc.240_241insGATC p.Gln81fs frameshift_variant 2/21 NP_009054.6 O75445-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.240_241insGATC p.Gln81fs frameshift_variant 2/721 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000366942.3 linkc.240_241insGATC p.Gln81fs frameshift_variant 2/211 ENSP00000355909.3 O75445-2
USH2AENST00000674083.1 linkc.240_241insGATC p.Gln81fs frameshift_variant 2/73 ENSP00000501296.1 O75445-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Usher syndrome type 2A Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2007- -
Pathogenic, no assertion criteria providedclinical testingFirmaLab, FirmaLab-- -
Retinitis pigmentosa 39 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2007- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs587776538; hg19: chr1-216595438; API