rs79444516

Positions:

chr1-215998957-C-G

Variant summary

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

The ENST00000307340.8(USH2A):c.6587G>C(p.Ser2196Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00684 in 1,613,082 control chromosomes in the GnomAD database, including 623 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 0.037 ( 347 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 276 hom. )

Consequence

USH2A
ENST00000307340.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.186

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=0.0024485886).

BP6

Variant 1-215998957-C-G is Benign according to our data. Variant chr1-215998957-C-G is described in ClinVar as [Benign]. Clinvar id is 48565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215998957-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 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.6587G>C	p.Ser2196Thr	missense_variant	34/72	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.6587G>C	p.Ser2196Thr	missense_variant	34/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.6587G>C	p.Ser2196Thr	missense_variant	34/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0372

AC:

5645

AN:

151928

Hom.:

347

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.0249

GnomAD3 exomes

AF:

0.00925

AC:

2322

AN:

250942

Hom.:

128

AF XY:

0.00658

AC XY:

893

AN XY:

135642

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.00487

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000423

Gnomad OTH exome

AF:

0.00458

GnomAD4 exome

AF:

0.00368

AC:

5376

AN:

1461036

Hom.:

276

Cov.:

AF XY:

0.00310

AC XY:

2255

AN XY:

726854

show subpopulations

Gnomad4 AFR exome

AF:

0.129

Gnomad4 AMR exome

AF:

0.00575

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000239

Gnomad4 OTH exome

AF:

0.00810

GnomAD4 genome

AF:

0.0373

AC:

5664

AN:

152046

Hom.:

347

Cov.:

AF XY:

0.0355

AC XY:

2642

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.130

Gnomad4 AMR

AF:

0.0113

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.00582

Hom.:

Bravo

AF:

0.0417

ESP6500AA

AF:

0.119

AC:

524

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0115

AC:

1397

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000533

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25262649, 22004887, 19683999, 27884173, 30245029) -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2022	Variant summary: USH2A c.6587G>C (p.Ser2196Thr) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0093 in 250942 control chromosomes, predominantly at a frequency of 0.13 within the African or African-American subpopulation in the gnomAD database, including 127 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in USH2A causing Usher Syndrome phenotype (0.011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.6587G>C in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 26, 2010	Ser2196Thr in exon 34 of USH2A: This variant has now been identified in 4/191 (2 .1%) individuals tested in our laboratory none of whom had a pathogenic USH2A va riant and one case had only conductive hearing loss inconsistent with an USH2A e tiology. In addition, all 4 individuals were Black or Hispanic suggesting this v ariant is very common in this population. -

Usher syndrome type 2A

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Retinitis pigmentosa 39

Benign:1

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

0.13

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

0.081

P;P

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.2

REVEL

Benign

0.13

Sift

Benign

0.23

Sift4G

Uncertain

0.014

Polyphen

0.80

Vest4

0.15

MPC

0.059

ClinPred

0.015

GERP RS

3.7

Varity_R

0.10

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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