chr1-215878891-G-T

Position:

chr1-215878891-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_206933.4(USH2A):c.8431C>A(p.Pro2811Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,614,024 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 7.27

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08946729).

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.8431C>A	p.Pro2811Thr	missense_variant	42/72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.8431C>A	p.Pro2811Thr	missense_variant	42/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.8431C>A	p.Pro2811Thr	missense_variant	42/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000291

AC:

AN:

251274

Hom.:

AF XY:

0.000398

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00222

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000130

AC:

190

AN:

1461820

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

137

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00191

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000823

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.000354

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 21, 2018	Variant classified as Uncertain Significance - Favor Benign. The p.Pro2811Thr va riant in USH2A has been reported by our laboratory in a family with hearing loss , however, it has been identified in 0.24% (39/16508) of South Asian chromosomes , including 2 homozygotes, by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs111033529). Computational prediction tools and con servation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, wh ile the clinical significance of the p.Pro2811Thr variant is uncertain, the freq uency data suggests it is more likely to be benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 04, 2024	Variant summary: USH2A c.8431C>A (p.Pro2811Thr) results in a non-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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251274 control chromosomes, predominantly at a frequency of 0.0022 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00029 vs 0.011), allowing no conclusion about variant significance. c.8431C>A has been reported in the literature in individuals affected with Usher Syndrome, reported as a VUS with unknown genotype (e.g. Hufnagel_2022) or as a compound heterozygous genotype, without evidence of causality in a single-gene testing setting (e.g. Sun_2018), in individuals affected with retinitis pigmentosa as a compound heterozygous genotype in settings of multi-gene panel testing (e.g. Wang_2017a) or WGS or WES testing with two additional USH2A variants reported (e.g. Carss_2017), or in compound heterozygous individuals affected with hearing loss with the second variant classified as benign (e.g.Wang_2017b) or other variants present in multiple genes (e.g. Park_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28041643, 35266249, 33269433, 29625443, 28838317, 28281779). ClinVar contains an entry for this variant (Variation ID: 48601). Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 04, 2017

- -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Dec 21, 2017

- -

Retinitis pigmentosa

Uncertain:1

Uncertain significance, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.089

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.33

Sift

Benign

0.31

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.80

MutPred

0.30

Gain of glycosylation at P2811 (P = 0.0678);

MVP

0.96

MPC

0.17

ClinPred

0.26

GERP RS

5.8

Varity_R

0.17

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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