1-215648597-C-T

Position:

chr1-215648597-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.14513G>A(p.Gly4838Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,038 control chromosomes in the GnomAD database, including 450 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. G4838R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.019 ( 71 hom., cov: 32)

Exomes 𝑓: 0.010 ( 379 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.908

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=0.0024906397).

BP6

Variant 1-215648597-C-T is Benign according to our data. Variant chr1-215648597-C-T is described in ClinVar as [Benign]. Clinvar id is 48439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215648597-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.14513G>A	p.Gly4838Glu	missense_variant	66/72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.14513G>A	p.Gly4838Glu	missense_variant	66/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.14513G>A	p.Gly4838Glu	missense_variant	66/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0186

AC:

2835

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0456

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00923

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0297

Gnomad SAS

AF:

0.0700

Gnomad FIN

AF:

0.00434

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00353

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0155

AC:

3901

AN:

251300

Hom.:

116

AF XY:

0.0174

AC XY:

2368

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.0471

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0188

Gnomad SAS exome

AF:

0.0693

Gnomad FIN exome

AF:

0.00300

Gnomad NFE exome

AF:

0.00386

Gnomad OTH exome

AF:

0.00962

GnomAD4 exome

AF:

0.0104

AC:

15168

AN:

1461790

Hom.:

379

Cov.:

AF XY:

0.0118

AC XY:

8580

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0472

Gnomad4 AMR exome

AF:

0.00362

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0506

Gnomad4 SAS exome

AF:

0.0665

Gnomad4 FIN exome

AF:

0.00253

Gnomad4 NFE exome

AF:

0.00432

Gnomad4 OTH exome

AF:

0.0117

GnomAD4 genome

AF:

0.0187

AC:

2842

AN:

152248

Hom.:

Cov.:

AF XY:

0.0194

AC XY:

1443

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0456

Gnomad4 AMR

AF:

0.00922

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.0298

Gnomad4 SAS

AF:

0.0703

Gnomad4 FIN

AF:

0.00434

Gnomad4 NFE

AF:

0.00353

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00507

Hom.:

Bravo

AF:

0.0183

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.0472

AC:

208

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.0174

AC:

2106

Asia WGS

AF:

0.0520

AC:

182

AN:

3478

EpiCase

AF:

0.00442

EpiControl

AF:

0.00320

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2011	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	Jul 26, 2010	Gly4838Glu in exon 66 of USH2A: This variant is not expected to have clinical si gnificance because this amino acid position in not conserved (chimp has a Glu at this amino acid position) and is listed in dbSNP (rs41315587 - no frequency dat a). In addition, this variant has been identified in 4/191 (2.1%) of individuals tested by our laboratory with at least 3/4 of Black or Hispanic background sugg esting this variant is a common benign variant in these populations. -

Usher syndrome type 2A

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Retinitis pigmentosa 39

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.74

CADD

Benign

5.7

DANN

Benign

0.17

DEOGEN2

Benign

0.016

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.060

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.75

PrimateAI

Benign

0.30

PROVEAN

Benign

1.4

REVEL

Benign

0.092

Sift

Benign

1.0

Sift4G

Benign

0.83

Polyphen

0.0

Vest4

0.050

MPC

0.035

ClinPred

0.0027

GERP RS

4.5

Varity_R

0.040

gMVP

0.37

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