NM_206933.4:c.240_241insGTAC

Variant names:

• chr1-216422096-G-GGTAC
• rs587776538
• NM_206933.4:c.240_241insGTAC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_206933.4(USH2A):​c.240_241insGTAC​(p.Gln81ValfsTer28) 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 no classification for the single variant (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: Not reported in ClinVar
• 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 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.240_241insGTAC	p.Gln81ValfsTer28	frameshift_variant	Exon 2 of 72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.240_241insGTAC	p.Gln81ValfsTer28	frameshift_variant	Exon 2 of 21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.240_241insGTAC	p.Gln81ValfsTer28	frameshift_variant	Exon 2 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.240_241insGTAC	p.Gln81ValfsTer28	frameshift_variant	Exon 2 of 21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.240_241insGTAC	p.Gln81ValfsTer28	frameshift_variant	Exon 2 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

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;