1-215628969-A-G

Position:

chr1-215628969-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The ENST00000307340.8(USH2A):c.15364T>C(p.Cys5122Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000532 in 1,613,996 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 2 hom. )

Consequence

USH2A
ENST00000307340.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 3.68

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.050745815).

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.15364T>C	p.Cys5122Arg	missense_variant	71/72	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.15364T>C	p.Cys5122Arg	missense_variant	71/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.15436T>C	p.Cys5146Arg	missense_variant	72/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000251

AC:

AN:

251440

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000484

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000556

AC:

813

AN:

1461748

Hom.:

Cov.:

AF XY:

0.000496

AC XY:

361

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000702

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000296

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000573

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000487

Hom.:

Bravo

AF:

0.000298

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 30, 2022	The p.Cys5122Arg variant in USH2A has been reported in one individual with hearing loss who also harbored a truncating variant in USH2A, though it was not clear whether these variants were confirmed in trans (Bonnet 2016). It has also been reported in two individuals who were found to have alternate explanations of their hearing loss or retinal dystrophy (Glockle 2013, LMM unpublished data). This variant has also been identified in 3 additional individuals with hearing loss by our laboratory; however, none of the individuals harbored a second variant on the remaining copy of USH2A. This variant has been identified in 0.047% (60/126682) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs111033402); however, its frequency is not high enough to rule out a pathogenic role. The cysteine (Cys) residue at position 5122 is not conserved in mammals or evolutionary distant species. Additional computational prediction tools do not provide strong support for or against an impact to the protein.In summary, while its frequency suggests it is more likley to be benign, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: None. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2023	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Identified in a patient with Usher syndrome in the published literature who also harbored another USH2A variant, although parental studies were not performed to determine the phase of these two variants (Bonnet et al., 2016); This variant is associated with the following publications: (PMID: 32141364, 23591405, 34426522, 27460420) -

Usher syndrome type 2A

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 13, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 27, 2021	NM_206933.2(USH2A):c.15364T>C(C5122R) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. C5122R has been observed in cases with relevant disease (PMID: 27460420, 23591405). Functional studies of this variant are not available in the literature. C5122R has been observed in population frequency databases (gnomAD NFE 0.05%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.15364T>C(C5122R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 12, 2022

- -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.064

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.46

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.34

M_CAP

Benign

0.019

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.98

D;D

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.69

REVEL

Benign

0.093

Sift

Benign

0.073

Sift4G

Uncertain

0.033

Polyphen

0.028

Vest4

0.34

MVP

0.51

MPC

0.043

ClinPred

0.029

GERP RS

4.5

Varity_R

0.18

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