rs6657250

Positions:

chr1-216046439-A-G

Variant summary

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

The NM_206933.4(USH2A):c.6317T>C(p.Ile2106Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 1,612,566 control chromosomes in the GnomAD database, including 346,400 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 Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 34553 hom., cov: 30)

Exomes 𝑓: 0.65 ( 311847 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.26

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=2.5621682E-6).

BP6

Variant 1-216046439-A-G is Benign according to our data. Variant chr1-216046439-A-G is described in ClinVar as [Benign]. Clinvar id is 167815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.758 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.6317T>C	p.Ile2106Thr	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.6317T>C	p.Ile2106Thr	missense_variant	32/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.6317T>C	p.Ile2106Thr	missense_variant	32/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.667

AC:

101217

AN:

151670

Hom.:

34516

Cov.:

show subpopulations

Gnomad AFR

AF:

0.765

Gnomad AMI

AF:

0.667

Gnomad AMR

AF:

0.506

Gnomad ASJ

AF:

0.679

Gnomad EAS

AF:

0.445

Gnomad SAS

AF:

0.501

Gnomad FIN

AF:

0.647

Gnomad MID

AF:

0.677

Gnomad NFE

AF:

0.676

Gnomad OTH

AF:

0.653

GnomAD3 exomes

AF:

0.594

AC:

149206

AN:

251068

Hom.:

46567

AF XY:

0.598

AC XY:

81090

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.771

Gnomad AMR exome

AF:

0.353

Gnomad ASJ exome

AF:

0.680

Gnomad EAS exome

AF:

0.441

Gnomad SAS exome

AF:

0.508

Gnomad FIN exome

AF:

0.648

Gnomad NFE exome

AF:

0.671

Gnomad OTH exome

AF:

0.625

GnomAD4 exome

AF:

0.649

AC:

947361

AN:

1460778

Hom.:

311847

Cov.:

AF XY:

0.645

AC XY:

469052

AN XY:

726748

show subpopulations

Gnomad4 AFR exome

AF:

0.771

Gnomad4 AMR exome

AF:

0.369

Gnomad4 ASJ exome

AF:

0.678

Gnomad4 EAS exome

AF:

0.444

Gnomad4 SAS exome

AF:

0.510

Gnomad4 FIN exome

AF:

0.653

Gnomad4 NFE exome

AF:

0.673

Gnomad4 OTH exome

AF:

0.650

GnomAD4 genome

AF:

0.667

AC:

101298

AN:

151788

Hom.:

34553

Cov.:

AF XY:

0.659

AC XY:

48880

AN XY:

74168

show subpopulations

Gnomad4 AFR

AF:

0.766

Gnomad4 AMR

AF:

0.505

Gnomad4 ASJ

AF:

0.679

Gnomad4 EAS

AF:

0.445

Gnomad4 SAS

AF:

0.500

Gnomad4 FIN

AF:

0.647

Gnomad4 NFE

AF:

0.676

Gnomad4 OTH

AF:

0.651

Alfa

AF:

0.662

Hom.:

82641

Bravo

AF:

0.657

TwinsUK

AF:

0.680

AC:

2523

ALSPAC

AF:

0.667

AC:

2569

ESP6500AA

AF:

0.761

AC:

3352

ESP6500EA

AF:

0.670

AC:

5758

ExAC

AF:

0.607

AC:

73632

Asia WGS

AF:

0.517

AC:

1800

AN:

3478

EpiCase

AF:

0.672

EpiControl

AF:

0.676

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2012	Inferred frequency = 157/386 (LMM data) -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 06, 2013	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 2A

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

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

0.046

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.029

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.12

MetaRNN

Benign

0.0000026

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.9

PrimateAI

Benign

0.27

PROVEAN

Benign

2.0

REVEL

Benign

0.13

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.021

MPC

0.034

ClinPred

0.0022

GERP RS

5.4

Varity_R

0.029

gMVP

0.17

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