rs696723

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.2137G>C(p.Gly713Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0202 in 1,613,916 control chromosomes in the GnomAD database, including 1,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G713G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.058 ( 655 hom., cov: 32)

Exomes 𝑓: 0.016 ( 779 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 5.51

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 -18 ACMG points.

PM1

In a domain Laminin EGF-like 4 (size 52) in uniprot entity USH2A_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0021301508).

BP6

Variant 1-216250933-C-G is Benign according to our data. Variant chr1-216250933-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 48484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216250933-C-G is described in Lovd as [Likely_benign]. Variant chr1-216250933-C-G is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.2137G>C	p.Gly713Arg	missense_variant	12/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6 linkuse as main transcript	c.2137G>C	p.Gly713Arg	missense_variant	12/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.2137G>C	p.Gly713Arg	missense_variant	12/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000366942.3 linkuse as main transcript	c.2137G>C	p.Gly713Arg	missense_variant	12/21	1		ENSP00000355909		O75445-2
USH2A	ENST00000674083.1 linkuse as main transcript	c.2137G>C	p.Gly713Arg	missense_variant	12/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0576

AC:

8754

AN:

152066

Hom.:

654

Cov.:

show subpopulations

Gnomad AFR

AF:

0.176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0277

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0205

Gnomad FIN

AF:

0.00632

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.0444

GnomAD3 exomes

AF:

0.0232

AC:

5814

AN:

250936

Hom.:

296

AF XY:

0.0207

AC XY:

2811

AN XY:

135614

show subpopulations

Gnomad AFR exome

AF:

0.181

Gnomad AMR exome

AF:

0.0144

Gnomad ASJ exome

AF:

0.0187

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.0215

Gnomad FIN exome

AF:

0.00689

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.0193

GnomAD4 exome

AF:

0.0163

AC:

23891

AN:

1461732

Hom.:

779

Cov.:

AF XY:

0.0159

AC XY:

11536

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.185

Gnomad4 AMR exome

AF:

0.0162

Gnomad4 ASJ exome

AF:

0.0178

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0209

Gnomad4 FIN exome

AF:

0.00618

Gnomad4 NFE exome

AF:

0.0115

Gnomad4 OTH exome

AF:

0.0233

GnomAD4 genome

AF:

0.0576

AC:

8765

AN:

152184

Hom.:

655

Cov.:

AF XY:

0.0563

AC XY:

4186

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.176

Gnomad4 AMR

AF:

0.0277

Gnomad4 ASJ

AF:

0.0170

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0205

Gnomad4 FIN

AF:

0.00632

Gnomad4 NFE

AF:

0.0105

Gnomad4 OTH

AF:

0.0440

Alfa

AF:

0.0186

Hom.:

Bravo

AF:

0.0655

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.174

AC:

768

ESP6500EA

AF:

0.0113

AC:

ExAC

AF:

0.0256

AC:

3104

Asia WGS

AF:

0.0310

AC:

107

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.0129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30245029, 15325563, 15241801, 22952768, 27884173, 10909849, 21228398, 22004887, 20981092, 21738395, 14676276, 22025579, 12112664, 25262649) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 18, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Usher syndrome type 2A

Benign:4

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Usher syndrome 2A (autosomal recessive, mild), in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:15325563). BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Retinitis pigmentosa 39

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Retinitis pigmentosa

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

T;.

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Pathogenic

3.8

H;H

MutationTaster

Benign

8.1e-7

P;P;P

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.7

D;D

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.34

MPC

0.25

ClinPred

0.057

GERP RS

4.2

Varity_R

0.84

gMVP

0.91

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