1-216365049-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_206933.4(USH2A):c.688G>A(p.Val230Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,613,260 control chromosomes in the GnomAD database, including 361 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V230L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 15 hom., cov: 32)

Exomes 𝑓: 0.021 ( 346 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: -0.0390

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.004126817).

BP6

Variant 1-216365049-C-T is Benign according to our data. Variant chr1-216365049-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48572.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=8, Uncertain_significance=1}. Variant chr1-216365049-C-T is described in Lovd as [Likely_benign]. Variant chr1-216365049-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.014 (2131/152212) while in subpopulation SAS AF= 0.0274 (132/4824). AF 95% confidence interval is 0.0236. There are 15 homozygotes in gnomad4. There are 1070 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.688G>A	p.Val230Met	missense_variant	Exon 4 of 72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A	NM_007123.6 link	c.688G>A	p.Val230Met	missense_variant	Exon 4 of 21		NP_009054.6	O75445-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USH2A	ENST00000307340.8 link	c.688G>A	p.Val230Met	missense_variant	Exon 4 of 72	1	NM_206933.4	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3 link	c.688G>A	p.Val230Met	missense_variant	Exon 4 of 21	1		ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1 link	c.688G>A	p.Val230Met	missense_variant	Exon 4 of 73			ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2131

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00439

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0273

Gnomad FIN

AF:

0.0218

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0193

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0152

AC:

3816

AN:

250800

Hom.:

AF XY:

0.0165

AC XY:

2242

AN XY:

135526

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.00675

Gnomad ASJ exome

AF:

0.0154

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.0224

Gnomad FIN exome

AF:

0.0220

Gnomad NFE exome

AF:

0.0186

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.0206

AC:

30026

AN:

1461048

Hom.:

346

Cov.:

AF XY:

0.0206

AC XY:

14955

AN XY:

726812

show subpopulations

Gnomad4 AFR exome

AF:

0.00347

Gnomad4 AMR exome

AF:

0.00707

Gnomad4 ASJ exome

AF:

0.0151

Gnomad4 EAS exome

AF:

0.00406

Gnomad4 SAS exome

AF:

0.0221

Gnomad4 FIN exome

AF:

0.0206

Gnomad4 NFE exome

AF:

0.0223

Gnomad4 OTH exome

AF:

0.0200

GnomAD4 genome

AF:

0.0140

AC:

2131

AN:

152212

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1070

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00438

Gnomad4 AMR

AF:

0.0109

Gnomad4 ASJ

AF:

0.0147

Gnomad4 EAS

AF:

0.00231

Gnomad4 SAS

AF:

0.0274

Gnomad4 FIN

AF:

0.0218

Gnomad4 NFE

AF:

0.0193

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0171

Hom.:

Bravo

AF:

0.0124

TwinsUK

AF:

0.0218

AC:

ALSPAC

AF:

0.0231

AC:

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0213

AC:

183

ExAC

AF:

0.0155

AC:

1878

Asia WGS

AF:

0.0270

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Aug 31, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

USH2A: BP4, BS1, BS2 -

not specified

Benign:4

Jan 07, 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. -

Sep 22, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Usher syndrome type 2A

Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.1

DANN

Benign

0.95

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.81

T;T

MetaRNN

Benign

0.0041

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.28

PROVEAN

Benign

0.0

N;N

REVEL

Benign

0.18

Sift

Benign

0.11

T;T

Sift4G

Benign

0.17

T;D

Polyphen

0.96

D;P

Vest4

0.054

MPC

0.072

ClinPred

0.0070

GERP RS

-1.4

Varity_R

0.029

gMVP

0.32

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