rs148556640

Positions:

chr1-215675303-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_206933.4(USH2A):c.12608A>G(p.Gln4203Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,614,126 control chromosomes in the GnomAD database, including 55 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0026 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 46 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.100

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 -18 ACMG points.

PM1

In a domain Fibronectin type-III 27 (size 104) in uniprot entity USH2A_HUMAN there are 22 pathogenic changes around while only 7 benign (76%) in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0027201176).

BP6

Variant 1-215675303-T-C is Benign according to our data. Variant chr1-215675303-T-C is described in ClinVar as [Benign]. Clinvar id is 48402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215675303-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00198 (2889/1461774) while in subpopulation EAS AF= 0.0298 (1184/39696). AF 95% confidence interval is 0.0284. There are 46 homozygotes in gnomad4_exome. There are 1408 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck.

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.12608A>G	p.Gln4203Arg	missense_variant	63/72	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.12608A>G	p.Gln4203Arg	missense_variant	63/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.12608A>G	p.Gln4203Arg	missense_variant	63/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00256

AC:

390

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0115

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0259

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00349

AC:

870

AN:

249220

Hom.:

AF XY:

0.00331

AC XY:

446

AN XY:

134884

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00937

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.0249

Gnomad NFE exome

AF:

0.000911

Gnomad OTH exome

AF:

0.00295

GnomAD4 exome

AF:

0.00198

AC:

2889

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

1408

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0298

Gnomad4 SAS exome

AF:

0.00103

Gnomad4 FIN exome

AF:

0.0222

Gnomad4 NFE exome

AF:

0.000292

Gnomad4 OTH exome

AF:

0.00151

GnomAD4 genome

AF:

0.00256

AC:

390

AN:

152352

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

286

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0116

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0259

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000993

Hom.:

Bravo

AF:

0.000468

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00352

AC:

427

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2019	This variant is associated with the following publications: (PMID: 19737284, 21835308, 25133751) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	USH2A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 11, 2012	Gln4203Arg in exon 63 of USH2A: This variant is not expected to have clinical si gnificance because it is has been identified in 3.4% (6/178) of Asian chromosome s in a broad population by the 1000 Genomes Project. (http://www.ncbi.nlm.nih.go v/variation/tools/1000genomes/; dbSNP rs148556640). -

Retinitis pigmentosa 39

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Usher syndrome type 2A

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

0.070

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

3.5

DANN

Benign

0.70

DEOGEN2

Benign

0.023

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.51

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.030

REVEL

Benign

0.043

Sift

Benign

0.63

Sift4G

Benign

0.53

Polyphen

0.0020

Vest4

0.029

MVP

0.81

MPC

0.032

ClinPred

0.0077

GERP RS

-0.25

Varity_R

0.048

gMVP

0.45

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