rs56385601

Positions:

chr1-215888964-A-G

Variant summary

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

The NM_206933.4(USH2A):c.7685T>C(p.Val2562Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00756 in 1,614,060 control chromosomes in the GnomAD database, including 62 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 (★★).

Frequency

Genomes: 𝑓 0.0059 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 58 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.93

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:

(HGNC:):

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=0.010328323).

BP6

Variant 1-215888964-A-G is Benign according to our data. Variant chr1-215888964-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 48589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215888964-A-G is described in Lovd as [Likely_benign]. Variant chr1-215888964-A-G is described in Lovd as [Likely_pathogenic].

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.7685T>C	p.Val2562Ala	missense_variant	41/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.7685T>C	p.Val2562Ala	missense_variant	41/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
	ENST00000414995.1 linkuse as main transcript	n.60+2323A>G		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1 linkuse as main transcript	c.7685T>C	p.Val2562Ala	missense_variant	41/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00587

AC:

893

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00213

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00615

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00480

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00867

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00649

AC:

1630

AN:

251140

Hom.:

AF XY:

0.00670

AC XY:

910

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00466

Gnomad ASJ exome

AF:

0.00984

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00245

Gnomad FIN exome

AF:

0.00675

Gnomad NFE exome

AF:

0.00950

Gnomad OTH exome

AF:

0.00670

GnomAD4 exome

AF:

0.00774

AC:

11317

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00788

AC XY:

5733

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00161

Gnomad4 AMR exome

AF:

0.00490

Gnomad4 ASJ exome

AF:

0.0116

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00262

Gnomad4 FIN exome

AF:

0.00614

Gnomad4 NFE exome

AF:

0.00879

Gnomad4 OTH exome

AF:

0.00634

GnomAD4 genome

AF:

0.00587

AC:

893

AN:

152212

Hom.:

Cov.:

AF XY:

0.00563

AC XY:

419

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00212

Gnomad4 AMR

AF:

0.00614

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00291

Gnomad4 FIN

AF:

0.00480

Gnomad4 NFE

AF:

0.00867

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.00864

Hom.:

Bravo

AF:

0.00593

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00860

AC:

ExAC

AF:

0.00651

AC:

790

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0106

EpiControl

AF:

0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

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	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	This variant is associated with the following publications: (PMID: 31266775, 19683999, 23484092, 18273898, 20052763, 22681893, 26927203, 22004887) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	USH2A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 17, 2011	Val2562Ala in exon 41 of USH2A: This variant has been reported in nine individua ls with a clinical diagnosis of Usher Syndrome types 1, 2 or 3 (Dreyer 2008, Jai jo 2009). However, several of these individuals already had other explanations f or their Usher syndrome (Jaijo 2009). In addition, this amino acid is not highly conserved acroos evolution, with the mouse and rat having an alanine at positio n 2562. In addition, this variant is listed in dbSNP (rs56385601 - no frequency data available) and has been identified in 6/278 (2.2%) probands tested by our l aboratory, none of whom had a variant on their second USH2A allele. In summary, this variant meets our criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2022	Variant summary: USH2A c.7685T>C (p.Val2562Ala) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0065 in 251140 control chromosomes, predominantly at a frequency of 0.0095 within the Non-Finnish European subpopulation in the gnomAD database, including 12 homozygotes. This frequency is close to that estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0065 vs 0.011), supporting a neutral outcome. Although reported frequently in the literature, to our knowledge, no occurrence of c.7685T>C in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one report listed this variant along with two other pathogenic alleles in an individual with Usher syndrome, supporting a benign outcome (example, Hagag_2020). Five 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. Based on the evidence outlined above, the variant was classified as benign. -

Usher syndrome type 2A

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 23, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

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

0.13

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.085

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.55

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-2.1

REVEL

Benign

0.10

Sift

Benign

0.79

Sift4G

Benign

0.21

Polyphen

0.0040

Vest4

0.71

MVP

0.84

MPC

0.037

ClinPred

0.0040

GERP RS

3.5

Varity_R

0.058

gMVP

0.25

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