rs58257972

Positions:

chr1-215625828-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the p.Ser5188Gly variant in the USH2A gene is 6.8% (2200/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA143409/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.0060 ( 24 hom., cov: 32)

Exomes 𝑓: 0.0092 ( 345 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:14

Conservation

PhyloP100: 5.55

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 -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.15562A>G	p.Ser5188Gly	missense_variant	72/72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.15562A>G	p.Ser5188Gly	missense_variant	72/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.15634A>G	p.Ser5212Gly	missense_variant	73/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00603

AC:

918

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00589

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0291

Gnomad SAS

AF:

0.0702

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00342

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.0125

AC:

3146

AN:

251432

Hom.:

AF XY:

0.0156

AC XY:

2114

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0186

Gnomad SAS exome

AF:

0.0712

Gnomad FIN exome

AF:

0.00300

Gnomad NFE exome

AF:

0.00376

Gnomad OTH exome

AF:

0.00896

GnomAD4 exome

AF:

0.00917

AC:

13402

AN:

1461784

Hom.:

345

Cov.:

AF XY:

0.0108

AC XY:

7872

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00215

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0493

Gnomad4 SAS exome

AF:

0.0684

Gnomad4 FIN exome

AF:

0.00253

Gnomad4 NFE exome

AF:

0.00423

Gnomad4 OTH exome

AF:

0.00924

GnomAD4 genome

AF:

0.00604

AC:

920

AN:

152290

Hom.:

Cov.:

AF XY:

0.00744

AC XY:

554

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00589

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.0293

Gnomad4 SAS

AF:

0.0704

Gnomad4 FIN

AF:

0.00433

Gnomad4 NFE

AF:

0.00343

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00437

Hom.:

Bravo

AF:

0.00434

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.0135

AC:

1633

Asia WGS

AF:

0.0480

AC:

168

AN:

3478

EpiCase

AF:

0.00431

EpiControl

AF:

0.00302

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	This variant is associated with the following publications: (PMID: 25356976) -

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 19, 2010	- -

Usher syndrome type 2A

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Usher syndrome

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Sep 17, 2018

The filtering allele frequency of the p.Ser5188Gly variant in the USH2A gene is 6.8% (2200/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 10, 2022

- -

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

0.11

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.7

REVEL

Benign

0.075

Sift

Benign

0.065

Sift4G

Uncertain

0.013

Polyphen

0.91

Vest4

0.13

MPC

0.065

ClinPred

0.023

GERP RS

5.9

Varity_R

0.20

gMVP

0.18

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