rs111033280

Variant names:

• chr1-216327637-C-G
• NM_206933.4:c.802G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-216327637-C-G
• chr1-216327637-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_Very_Strong PM2 PP3_Strong PP5_Moderate

The NM_206933.4(USH2A):​c.802G>C​(p.Gly268Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.49

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 16 ACMG points.

• PS1: Transcript NM_206933.4 (USH2A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 48592
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 1-216327637-C-G is Pathogenic according to our data. Variant chr1-216327637-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2090409.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-216327637-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.802G>C	p.Gly268Arg	missense_variant	Exon 5 of 72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.802G>C	p.Gly268Arg	missense_variant	Exon 5 of 21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.802G>C	p.Gly268Arg	missense_variant	Exon 5 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.802G>C	p.Gly268Arg	missense_variant	Exon 5 of 21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.802G>C	p.Gly268Arg	missense_variant	Exon 5 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 268 of the USH2A protein (p.Gly268Arg). This missense change has been observed in individuals with Usher syndrome (PMID: 25356976, 29490346, 29625443). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	2.9	M;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.83		Gain of MoRF binding (P = 0.0417);Gain of MoRF binding (P = 0.0417);
MVP		0.93
MPC		0.25
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.80
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-216500979; COSMIC: COSV56386823;