rs587776538

Positions:

• chr1-216422096-G-GGATC
• chr1-216422096-G-GGTAC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 1.26

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]

ACMG classification

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
USH2A	NM_206933.4	c.240_241insGATC	p.Gln81fs	frameshift_variant	2/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.240_241insGATC	p.Gln81fs	frameshift_variant	2/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.240_241insGATC	p.Gln81fs	frameshift_variant	2/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.240_241insGATC	p.Gln81fs	frameshift_variant	2/21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.240_241insGATC	p.Gln81fs	frameshift_variant	2/73			ENSP00000501296.1

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

Submissions by phenotype

Usher syndrome type 2A Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2007	- -
Pathogenic, no assertion criteria provided	clinical testing	FirmaLab, FirmaLab	-	- -

Retinitis pigmentosa 39 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776538; hg19: chr1-216595438;