1-215838100-C-T

Position:

chr1-215838100-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_206933.4(USH2A):c.9262G>A(p.Glu3088Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00726 in 1,612,766 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0074 ( 53 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.19

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014042646).

BP6

Variant 1-215838100-C-T is Benign according to our data. Variant chr1-215838100-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 48618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215838100-C-T is described in Lovd as [Likely_benign]. Variant chr1-215838100-C-T is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.9262G>A	p.Glu3088Lys	missense_variant	47/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.9262G>A	p.Glu3088Lys	missense_variant	47/72	1	NM_206933.4	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.9262G>A	p.Glu3088Lys	missense_variant	47/73				O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00597

AC:

908

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00636

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0133

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00789

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00636

AC:

1599

AN:

251272

Hom.:

AF XY:

0.00667

AC XY:

906

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00512

Gnomad ASJ exome

AF:

0.00903

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00304

Gnomad FIN exome

AF:

0.00998

Gnomad NFE exome

AF:

0.00836

Gnomad OTH exome

AF:

0.00848

GnomAD4 exome

AF:

0.00740

AC:

10803

AN:

1460516

Hom.:

Cov.:

AF XY:

0.00740

AC XY:

5377

AN XY:

726660

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00543

Gnomad4 ASJ exome

AF:

0.00781

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00292

Gnomad4 FIN exome

AF:

0.00903

Gnomad4 NFE exome

AF:

0.00817

Gnomad4 OTH exome

AF:

0.00749

GnomAD4 genome

AF:

0.00596

AC:

907

AN:

152250

Hom.:

Cov.:

AF XY:

0.00610

AC XY:

454

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00636

Gnomad4 ASJ

AF:

0.00807

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0133

Gnomad4 NFE

AF:

0.00789

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00739

Hom.:

Bravo

AF:

0.00552

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00637

AC:

773

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00949

EpiControl

AF:

0.00913

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: USH2A c.9262G>A (p.Glu3088Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0064 in 251272 control chromosomes in the gnomAD database, including 12 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0064 vs 0.011), allowing no conclusion about variant significance. Although this variant has been reported in the literature, to our knowledge, no occurrence of c.9262G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 26, 2012	Glu3088Lys in exon 47 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (47/7020) of European American chromosomes and 0.2% (7/3738) of African American chromosomes from a broad popu lation by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; (rs56056328). It addition, it occurrs at an equal frequency in cases and contro ls (McGee 2010; Dreyer 2008). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2015	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	This variant is associated with the following publications: (PMID: 21909055, 20507924, 26927203, 18273898, 22004887, 21559123, 19683999, 25999674) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	USH2A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Usher syndrome type 2A

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.7

MutationTaster

Benign

0.97

D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.28

Sift

Uncertain

0.012

Sift4G

Uncertain

0.034

Polyphen

1.0

Vest4

0.82

MVP

0.94

MPC

0.046

ClinPred

0.022

GERP RS

4.1

Varity_R

0.32

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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