rs59174500

Positions:

chr1-215878864-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The ENST00000307340.8(USH2A):c.8458G>A(p.Val2820Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,614,010 control chromosomes in the GnomAD database, including 7 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 5 hom. )

Consequence

USH2A
ENST00000307340.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.183

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 -14 ACMG points.

PM1

In a domain Fibronectin type-III 15 (size 103) in uniprot entity USH2A_HUMAN there are 16 pathogenic changes around while only 6 benign (73%) in ENST00000307340.8

BP4

Computational evidence support a benign effect (MetaRNN=0.010608584).

BP6

Variant 1-215878864-C-T is Benign according to our data. Variant chr1-215878864-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215878864-C-T is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.8458G>A	p.Val2820Ile	missense_variant	42/72	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.8458G>A	p.Val2820Ile	missense_variant	42/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.8458G>A	p.Val2820Ile	missense_variant	42/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00364

AC:

554

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00210

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00104

AC:

262

AN:

251214

Hom.:

AF XY:

0.000722

AC XY:

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.0130

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000380

AC:

555

AN:

1461816

Hom.:

Cov.:

AF XY:

0.000327

AC XY:

238

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0110

Gnomad4 AMR exome

AF:

0.00112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000728

Gnomad4 OTH exome

AF:

0.000844

GnomAD4 genome

AF:

0.00365

AC:

556

AN:

152194

Hom.:

Cov.:

AF XY:

0.00348

AC XY:

259

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0124

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.00447

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00120

AC:

146

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Usher syndrome type 2A

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 08, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Val2820Ile in Exon 42 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 1.4% (54/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs59174500). -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 20, 2022

- -

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

0.069

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.3

DANN

Benign

0.37

DEOGEN2

Benign

0.042

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.46

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

0.10

REVEL

Benign

0.019

Sift

Benign

0.54

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.067

MVP

0.41

MPC

0.027

ClinPred

0.0012

GERP RS

0.065

Varity_R

0.024

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