chr1-215970707-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_206933.4(USH2A):c.6875G>A(p.Arg2292His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,613,568 control chromosomes in the GnomAD database, including 781 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2292C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.020 ( 48 hom., cov: 32)

Exomes 𝑓: 0.028 ( 733 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.0800

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 Fibronectin type-III 9 (size 87) in uniprot entity USH2A_HUMAN there are 41 pathogenic changes around while only 8 benign (84%) in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.002261877).

BP6

Variant 1-215970707-C-T is Benign according to our data. Variant chr1-215970707-C-T is described in ClinVar as [Benign]. Clinvar id is 48571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215970707-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0195 (2972/152152) while in subpopulation NFE AF= 0.0288 (1956/67996). AF 95% confidence interval is 0.0277. There are 48 homozygotes in gnomad4. There are 1454 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.6875G>A	p.Arg2292His	missense_variant	Exon 36 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.6875G>A	p.Arg2292His	missense_variant	Exon 36 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.6875G>A	p.Arg2292His	missense_variant	Exon 36 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0195

AC:

2972

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00507

Gnomad AMI

AF:

0.0910

Gnomad AMR

AF:

0.00820

Gnomad ASJ

AF:

0.0109

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.0433

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0288

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.0214

AC:

5374

AN:

251062

Hom.:

AF XY:

0.0222

AC XY:

3008

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.00455

Gnomad AMR exome

AF:

0.00606

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0149

Gnomad FIN exome

AF:

0.0442

Gnomad NFE exome

AF:

0.0303

Gnomad OTH exome

AF:

0.0212

GnomAD4 exome

AF:

0.0276

AC:

40391

AN:

1461416

Hom.:

733

Cov.:

AF XY:

0.0271

AC XY:

19675

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.00383

Gnomad4 AMR exome

AF:

0.00654

Gnomad4 ASJ exome

AF:

0.00976

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0159

Gnomad4 FIN exome

AF:

0.0441

Gnomad4 NFE exome

AF:

0.0311

Gnomad4 OTH exome

AF:

0.0235

GnomAD4 genome

AF:

0.0195

AC:

2972

AN:

152152

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

1454

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00506

Gnomad4 AMR

AF:

0.00818

Gnomad4 ASJ

AF:

0.0109

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.0141

Gnomad4 FIN

AF:

0.0433

Gnomad4 NFE

AF:

0.0288

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0263

Hom.:

Bravo

AF:

0.0167

TwinsUK

AF:

0.0280

AC:

104

ALSPAC

AF:

0.0353

AC:

136

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0303

AC:

261

ExAC

AF:

0.0224

AC:

2719

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0256

EpiControl

AF:

0.0240

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Sep 20, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified

Benign:2

Jun 24, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 17, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Usher syndrome type 2A

Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 04, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 39

Benign:1

Nov 04, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.90

DANN

Benign

0.86

DEOGEN2

Benign

0.022

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.55

PrimateAI

Benign

0.20

PROVEAN

Benign

1.0

REVEL

Benign

0.056

Sift

Benign

0.61

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.044

MPC

0.034

ClinPred

0.0022

GERP RS

0.79

Varity_R

0.027

gMVP

0.26

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