1-215728168-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_206933.4(USH2A):c.11928G>A(p.Thr3976Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,614,106 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T3976T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0096 ( 19 hom., cov: 32)

Exomes 𝑓: 0.011 ( 128 hom. )

Consequence

USH2A
NM_206933.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: -1.43

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 1-215728168-C-T is Benign according to our data. Variant chr1-215728168-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48386.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=6, Uncertain_significance=1}. Variant chr1-215728168-C-T is described in Lovd as [Benign]. Variant chr1-215728168-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.43 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.11928G>A	p.Thr3976Thr	synonymous_variant	Exon 61 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.11928G>A	p.Thr3976Thr	synonymous_variant	Exon 61 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.11928G>A	p.Thr3976Thr	synonymous_variant	Exon 61 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00965

AC:

1468

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.0308

Gnomad AMR

AF:

0.00635

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.0429

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00952

AC:

2392

AN:

251312

Hom.:

AF XY:

0.00998

AC XY:

1356

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.00376

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.000870

Gnomad SAS exome

AF:

0.00500

Gnomad FIN exome

AF:

0.0402

Gnomad NFE exome

AF:

0.00972

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0109

AC:

15885

AN:

1461880

Hom.:

128

Cov.:

AF XY:

0.0108

AC XY:

7882

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00152

Gnomad4 AMR exome

AF:

0.00347

Gnomad4 ASJ exome

AF:

0.00210

Gnomad4 EAS exome

AF:

0.000982

Gnomad4 SAS exome

AF:

0.00544

Gnomad4 FIN exome

AF:

0.0399

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.00907

GnomAD4 genome

AF:

0.00964

AC:

1467

AN:

152226

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

822

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.00222

Gnomad4 AMR

AF:

0.00634

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.00560

Gnomad4 FIN

AF:

0.0429

Gnomad4 NFE

AF:

0.0109

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.00818

Hom.:

Bravo

AF:

0.00624

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00818

EpiControl

AF:

0.00812

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Jul 02, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 04, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2015

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. -

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

USH2A: BP4, BP7, BS1, BS2 -

Oct 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Usher syndrome type 2A

Uncertain:1Benign:1

Molecular Genetics Laboratory; Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Dec 30, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.6

DANN

Benign

0.36

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