rs56038610

Positions:

chr1-215634665-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_206933.4(USH2A):c.15091C>T(p.Arg5031Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,614,150 control chromosomes in the GnomAD database, including 343 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 24 hom., cov: 32)

Exomes 𝑓: 0.019 ( 319 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 3.18

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028478205).

BP6

Variant 1-215634665-G-A is Benign according to our data. Variant chr1-215634665-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215634665-G-A is described in Lovd as [Likely_benign]. Variant chr1-215634665-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0133 (2029/152266) while in subpopulation NFE AF= 0.0174 (1184/68026). AF 95% confidence interval is 0.0166. There are 24 homozygotes in gnomad4. There are 1108 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.15091C>T	p.Arg5031Trp	missense_variant	70/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.15091C>T	p.Arg5031Trp	missense_variant	70/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.15091C>T	p.Arg5031Trp	missense_variant	70/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2030

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00316

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00975

Gnomad FIN

AF:

0.0555

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0174

Gnomad OTH

AF:

0.00960

GnomAD3 exomes

AF:

0.0156

AC:

3921

AN:

251424

Hom.:

AF XY:

0.0158

AC XY:

2149

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0102

Gnomad FIN exome

AF:

0.0537

Gnomad NFE exome

AF:

0.0192

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0186

AC:

27246

AN:

1461884

Hom.:

319

Cov.:

AF XY:

0.0181

AC XY:

13147

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00251

Gnomad4 AMR exome

AF:

0.00288

Gnomad4 ASJ exome

AF:

0.00203

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0108

Gnomad4 FIN exome

AF:

0.0508

Gnomad4 NFE exome

AF:

0.0201

Gnomad4 OTH exome

AF:

0.0152

GnomAD4 genome

AF:

0.0133

AC:

2029

AN:

152266

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1108

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00315

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00976

Gnomad4 FIN

AF:

0.0555

Gnomad4 NFE

AF:

0.0174

Gnomad4 OTH

AF:

0.00950

Alfa

AF:

0.0152

Hom.:

Bravo

AF:

0.00952

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0244

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0174

AC:

150

ExAC

AF:

0.0157

AC:

1908

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0142

EpiControl

AF:

0.0137

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other: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	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	USH2A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2018	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 07, 2013	Arg5031Trp in exon 70 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 1.3% (167/12839) of chromosomes fr om a broad population by the NHLBI Exome sequencing project (http://evs.gs.washi ngton.edu/EVS/; dbSNP rs56038610) and is reported as benign in Dreyer et al. 200 8. -
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:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 29, 2019	- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.55

REVEL

Benign

0.089

Sift

Benign

0.12

Sift4G

Uncertain

0.028

Polyphen

0.88

Vest4

0.084

MPC

0.067

ClinPred

0.017

GERP RS

2.9

Varity_R

0.057

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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