rs41277194

Positions:

chr1-215838066-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000307340.8(USH2A):c.9296A>G(p.Asn3099Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0302 in 1,613,804 control chromosomes in the GnomAD database, including 883 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 145 hom., cov: 32)

Exomes 𝑓: 0.029 ( 738 hom. )

Consequence

USH2A
ENST00000307340.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.10

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 glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity USH2A_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.0027686954).

BP6

Variant 1-215838066-T-C is Benign according to our data. Variant chr1-215838066-T-C is described in ClinVar as [Benign]. Clinvar id is 48620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215838066-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0669 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.9296A>G	p.Asn3099Ser	missense_variant	47/72	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.9296A>G	p.Asn3099Ser	missense_variant	47/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.9296A>G	p.Asn3099Ser	missense_variant	47/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0395

AC:

6013

AN:

152120

Hom.:

142

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0688

Gnomad AMI

AF:

0.0462

Gnomad AMR

AF:

0.0388

Gnomad ASJ

AF:

0.0413

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0262

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0290

Gnomad OTH

AF:

0.0489

GnomAD3 exomes

AF:

0.0276

AC:

6943

AN:

251320

Hom.:

104

AF XY:

0.0269

AC XY:

3649

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.0689

Gnomad AMR exome

AF:

0.0261

Gnomad ASJ exome

AF:

0.0405

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00470

Gnomad FIN exome

AF:

0.0273

Gnomad NFE exome

AF:

0.0314

Gnomad OTH exome

AF:

0.0346

GnomAD4 exome

AF:

0.0292

AC:

42658

AN:

1461566

Hom.:

738

Cov.:

AF XY:

0.0286

AC XY:

20798

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.0746

Gnomad4 AMR exome

AF:

0.0277

Gnomad4 ASJ exome

AF:

0.0420

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00365

Gnomad4 FIN exome

AF:

0.0275

Gnomad4 NFE exome

AF:

0.0304

Gnomad4 OTH exome

AF:

0.0331

GnomAD4 genome

AF:

0.0396

AC:

6028

AN:

152238

Hom.:

145

Cov.:

AF XY:

0.0392

AC XY:

2915

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0690

Gnomad4 AMR

AF:

0.0388

Gnomad4 ASJ

AF:

0.0413

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.0262

Gnomad4 NFE

AF:

0.0290

Gnomad4 OTH

AF:

0.0488

Alfa

AF:

0.0313

Hom.:

145

Bravo

AF:

0.0436

TwinsUK

AF:

0.0256

AC:

ALSPAC

AF:

0.0309

AC:

119

ESP6500AA

AF:

0.0697

AC:

307

ESP6500EA

AF:

0.0305

AC:

262

ExAC

AF:

0.0283

AC:

3432

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0303

EpiControl

AF:

0.0356

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2009	- -
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	Eurofins Ntd Llc (ga)	May 27, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Usher syndrome type 2A

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

MutationTaster

Benign

0.65

D;D

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.085

Sift

Benign

0.050

Sift4G

Uncertain

0.011

Polyphen

0.18

Vest4

0.13

MPC

0.033

ClinPred

0.021

GERP RS

2.6

Varity_R

0.089

gMVP

0.34

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