chr1-216046516-C-A

Position:

chr1-216046516-C-A

Variant summary

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

The NM_206933.4(USH2A):c.6240G>T(p.Lys2080Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00703 in 1,613,826 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

Frequency

Genomes: 𝑓 0.0073 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 52 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:15

Conservation

PhyloP100: 0.412

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=0.008006275).

BP6

Variant 1-216046516-C-A is Benign according to our data. Variant chr1-216046516-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 48555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216046516-C-A is described in Lovd as [Likely_benign]. Variant chr1-216046516-C-A is described in Lovd as [Benign]. Variant chr1-216046516-C-A is described in Lovd as [Pathogenic].

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.6240G>T	p.Lys2080Asn	missense_variant	32/72	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.6240G>T	p.Lys2080Asn	missense_variant	32/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.6240G>T	p.Lys2080Asn	missense_variant	32/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00730

AC:

1111

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00952

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00956

Gnomad ASJ

AF:

0.00750

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00734

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00556

AC:

1396

AN:

251140

Hom.:

AF XY:

0.00520

AC XY:

705

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.0102

Gnomad AMR exome

AF:

0.00509

Gnomad ASJ exome

AF:

0.00655

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00203

Gnomad NFE exome

AF:

0.00780

Gnomad OTH exome

AF:

0.00702

GnomAD4 exome

AF:

0.00700

AC:

10236

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00680

AC XY:

4946

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00974

Gnomad4 AMR exome

AF:

0.00479

Gnomad4 ASJ exome

AF:

0.00742

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000881

Gnomad4 FIN exome

AF:

0.00198

Gnomad4 NFE exome

AF:

0.00798

Gnomad4 OTH exome

AF:

0.00674

GnomAD4 genome

AF:

0.00730

AC:

1111

AN:

152216

Hom.:

Cov.:

AF XY:

0.00708

AC XY:

527

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00949

Gnomad4 AMR

AF:

0.00955

Gnomad4 ASJ

AF:

0.00750

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00734

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.00726

Hom.:

Bravo

AF:

0.00775

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.00930

AC:

ExAC

AF:

0.00592

AC:

719

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00834

EpiControl

AF:

0.00771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	USH2A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2018	This variant is associated with the following publications: (PMID: 25412400, 18273898) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 14, 2012	Lys2080Asn in Exon 32 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 1.1% (41/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs114402911). As expected, this variant has b een reported in equal frequencies in cases and controls (Booij 2010, Clark 2010, Dreyer 2008, McGee 2010). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2022	Variant summary: USH2A c.6240G>T (p.Lys2080Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0056 in 251140 control chromosomes, predominantly at a frequency of 0.01 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. This frequency is almost close to that estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0056 vs 0.011), supporting a benign outcome. To our knowledge, no penetrant association of c.6240G>T in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Usher syndrome type 2A

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Retinitis pigmentosa

Uncertain:1

Uncertain significance, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Retinitis pigmentosa 39

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0080

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.6

REVEL

Benign

0.11

Sift

Benign

0.041

Sift4G

Uncertain

0.013

Polyphen

0.88

Vest4

0.087

MutPred

0.47

Loss of methylation at K2080 (P = 3e-04);

MVP

0.87

MPC

0.046

ClinPred

0.025

GERP RS

0.71

Varity_R

0.12

gMVP

0.42

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