1-216175422-C-T

Position:

chr1-216175422-C-T

Variant summary

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

The NM_206933.4(USH2A):c.4457G>A(p.Arg1486Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,613,420 control chromosomes in the GnomAD database, including 326,396 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1486G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.63 ( 30324 hom., cov: 32)

Exomes 𝑓: 0.63 ( 296072 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.52

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=1.6309556E-6).

BP6

Variant 1-216175422-C-T is Benign according to our data. Variant chr1-216175422-C-T is described in ClinVar as [Benign]. Clinvar id is 177992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.4457G>A	p.Arg1486Lys	missense_variant	21/72	ENST00000307340.8
USH2A	NM_007123.6 linkuse as main transcript	c.4457G>A	p.Arg1486Lys	missense_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.4457G>A	p.Arg1486Lys	missense_variant	21/72	1	NM_206933.4	P1	O75445-1
USH2A	ENST00000366942.3 linkuse as main transcript	c.4457G>A	p.Arg1486Lys	missense_variant	21/21	1			O75445-2
USH2A	ENST00000674083.1 linkuse as main transcript	c.4457G>A	p.Arg1486Lys	missense_variant	21/73				O75445-3

Frequencies

GnomAD3 genomes

AF:

0.629

AC:

95572

AN:

151932

Hom.:

30303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.577

Gnomad AMI

AF:

0.799

Gnomad AMR

AF:

0.661

Gnomad ASJ

AF:

0.587

Gnomad EAS

AF:

0.762

Gnomad SAS

AF:

0.709

Gnomad FIN

AF:

0.728

Gnomad MID

AF:

0.563

Gnomad NFE

AF:

0.623

Gnomad OTH

AF:

0.626

GnomAD3 exomes

AF:

0.661

AC:

165406

AN:

250414

Hom.:

55252

AF XY:

0.659

AC XY:

89168

AN XY:

135334

show subpopulations

Gnomad AFR exome

AF:

0.581

Gnomad AMR exome

AF:

0.716

Gnomad ASJ exome

AF:

0.576

Gnomad EAS exome

AF:

0.781

Gnomad SAS exome

AF:

0.699

Gnomad FIN exome

AF:

0.722

Gnomad NFE exome

AF:

0.623

Gnomad OTH exome

AF:

0.630

GnomAD4 exome

AF:

0.635

AC:

927401

AN:

1461370

Hom.:

296072

Cov.:

AF XY:

0.635

AC XY:

461871

AN XY:

726974

show subpopulations

Gnomad4 AFR exome

AF:

0.574

Gnomad4 AMR exome

AF:

0.710

Gnomad4 ASJ exome

AF:

0.575

Gnomad4 EAS exome

AF:

0.799

Gnomad4 SAS exome

AF:

0.698

Gnomad4 FIN exome

AF:

0.712

Gnomad4 NFE exome

AF:

0.621

Gnomad4 OTH exome

AF:

0.633

GnomAD4 genome

AF:

0.629

AC:

95627

AN:

152050

Hom.:

30324

Cov.:

AF XY:

0.636

AC XY:

47233

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.576

Gnomad4 AMR

AF:

0.662

Gnomad4 ASJ

AF:

0.587

Gnomad4 EAS

AF:

0.762

Gnomad4 SAS

AF:

0.710

Gnomad4 FIN

AF:

0.728

Gnomad4 NFE

AF:

0.623

Gnomad4 OTH

AF:

0.627

Alfa

AF:

0.622

Hom.:

60175

Bravo

AF:

0.624

TwinsUK

AF:

0.621

AC:

2302

ALSPAC

AF:

0.625

AC:

2408

ESP6500AA

AF:

0.596

AC:

2626

ESP6500EA

AF:

0.612

AC:

5261

ExAC

AF:

0.657

AC:

79731

Asia WGS

AF:

0.731

AC:

2543

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2012	Inferred frequency = 141/386 (LMM data) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Usher syndrome type 2A

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 18, 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

0.084

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.63

CADD

Benign

9.8

DANN

Benign

0.90

DEOGEN2

Benign

0.021

T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

0.0000016

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.16

N;N

REVEL

Benign

0.024

Sift

Benign

0.42

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.094

B;B

Vest4

0.044

MPC

0.032

ClinPred

0.0025

GERP RS

-2.2

Varity_R

0.085

gMVP

0.34

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