chr1-215675245-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_206933.4(USH2A):c.12666A>G(p.Thr4222Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,613,974 control chromosomes in the GnomAD database, including 114,339 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9403 hom., cov: 33)

Exomes 𝑓: 0.38 ( 104936 hom. )

Consequence

USH2A
NM_206933.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.426

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 1-215675245-T-C is Benign according to our data. Variant chr1-215675245-T-C is described in ClinVar as [Benign]. Clinvar id is 48403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215675245-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.426 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.12666A>G	p.Thr4222Thr	synonymous_variant	Exon 63 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.12666A>G	p.Thr4222Thr	synonymous_variant	Exon 63 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.12666A>G	p.Thr4222Thr	synonymous_variant	Exon 63 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.339

AC:

51541

AN:

152062

Hom.:

9406

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.407

Gnomad AMR

AF:

0.416

Gnomad ASJ

AF:

0.307

Gnomad EAS

AF:

0.305

Gnomad SAS

AF:

0.299

Gnomad FIN

AF:

0.402

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.391

Gnomad OTH

AF:

0.331

GnomAD3 exomes

AF:

0.370

AC:

92457

AN:

250022

Hom.:

17788

AF XY:

0.368

AC XY:

49684

AN XY:

135110

show subpopulations

Gnomad AFR exome

AF:

0.213

Gnomad AMR exome

AF:

0.470

Gnomad ASJ exome

AF:

0.320

Gnomad EAS exome

AF:

0.326

Gnomad SAS exome

AF:

0.302

Gnomad FIN exome

AF:

0.401

Gnomad NFE exome

AF:

0.386

Gnomad OTH exome

AF:

0.372

GnomAD4 exome

AF:

0.375

AC:

548818

AN:

1461794

Hom.:

104936

Cov.:

AF XY:

0.374

AC XY:

271649

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.211

Gnomad4 AMR exome

AF:

0.462

Gnomad4 ASJ exome

AF:

0.313

Gnomad4 EAS exome

AF:

0.255

Gnomad4 SAS exome

AF:

0.307

Gnomad4 FIN exome

AF:

0.399

Gnomad4 NFE exome

AF:

0.388

Gnomad4 OTH exome

AF:

0.360

GnomAD4 genome

AF:

0.339

AC:

51546

AN:

152180

Hom.:

9403

Cov.:

AF XY:

0.339

AC XY:

25210

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.219

Gnomad4 AMR

AF:

0.416

Gnomad4 ASJ

AF:

0.307

Gnomad4 EAS

AF:

0.305

Gnomad4 SAS

AF:

0.297

Gnomad4 FIN

AF:

0.402

Gnomad4 NFE

AF:

0.391

Gnomad4 OTH

AF:

0.333

Alfa

AF:

0.372

Hom.:

13908

Bravo

AF:

0.335

Asia WGS

AF:

0.275

AC:

953

AN:

3478

EpiCase

AF:

0.376

EpiControl

AF:

0.374

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jan 21, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 10, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 18, 2011

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. -

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Usher syndrome type 2A

Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

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

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.33

DANN

Benign

0.40

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