rs117461552

Positions:

chr1-215993142-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_206933.4(USH2A):c.6683T>A(p.Val2228Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,613,966 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 3 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.91

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]

USH2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009736955).

BP6

Variant 1-215993142-A-T is Benign according to our data. Variant chr1-215993142-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 48566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215993142-A-T is described in Lovd as [Likely_pathogenic]. Variant chr1-215993142-A-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.6683T>A	p.Val2228Glu	missense_variant	35/72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.6683T>A	p.Val2228Glu	missense_variant	35/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.6683T>A	p.Val2228Glu	missense_variant	35/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00929

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000510

AC:

128

AN:

251052

Hom.:

AF XY:

0.000405

AC XY:

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00686

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000224

AC:

327

AN:

1461788

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

163

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00791

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000315

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00912

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000238

Hom.:

Bravo

AF:

0.000317

ExAC

AF:

0.000552

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Val2228Glu in Exon 35 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 4.2% (5/120) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs11 7461552). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2022	Variant summary: USH2A c.6683T>A (p.Val2228Glu) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 251052 control chromosomes, predominantly at a frequency of 0.0069 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00051 vs 0.011), allowing no conclusion about variant significance. c.6683T>A has been reported in the literature with conflicting interpretations (VUS/Likely Benign) along with other variants in the USH2A gene (phase not specified) in cohorts of individuals undergoing whole exome sequencing (WES) for genetic evaluation of Retinal Degeneration (RD) and in particular with Retinitis Pigmentosa (example, Ma_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Usher syndrome type 2A

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Retinitis pigmentosa 39

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

Eigen

Benign

-0.046

Eigen_PC

Benign

-0.065

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0097

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.18

Sift

Benign

0.030

Sift4G

Uncertain

0.0060

Polyphen

0.87

Vest4

0.26

MVP

0.94

MPC

0.041

ClinPred

0.099

GERP RS

4.8

Varity_R

0.22

gMVP

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over