1-215879002-C-T

Position:

chr1-215879002-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the p.Ala2774Thr variant in the USH2A gene is 0.13% for European Finnish chromosome by gnomAD (35/25118), and one homozygous European (Finnish) individual and one homozygous European (non-Finnish) individual (BS1_Supporting). The REVEL computational prediction analysis tool predicted a score of 0.052, which meets the threshold to apply BP4. In summary, the HL EP classified this variant as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA143621/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.00057 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00072 ( 1 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:8

Conservation

PhyloP100: 1.38

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

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.8320G>A	p.Ala2774Thr	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.8320G>A	p.Ala2774Thr	missense_variant	42/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.8320G>A	p.Ala2774Thr	missense_variant	42/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000544

AC:

136

AN:

250090

Hom.:

AF XY:

0.000577

AC XY:

AN XY:

135254

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.000694

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000718

AC:

1050

AN:

1461772

Hom.:

Cov.:

AF XY:

0.000683

AC XY:

497

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000499

Gnomad4 FIN exome

AF:

0.00122

Gnomad4 NFE exome

AF:

0.000785

Gnomad4 OTH exome

AF:

0.00101

GnomAD4 genome

AF:

0.000565

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000612

Hom.:

Bravo

AF:

0.000382

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000544

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000474

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Usher syndrome type 2A

Uncertain:1Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 19, 2021	NM_206933.2(USH2A):c.8320G>A(A2774T) is a missense variant classified as a variant of uncertain significance. A2774T has been observed in cases of USH2A-related disorders (PMID: 25133751, 28041643). Functional studies on this variant are not available. A2774T has been observed in population frequency databases (gnomAD: EUR 0.14%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.8320G>A(A2774T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	USH2A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 32707200, 28041643) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Retinal dystrophy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 17, 2010

- -

Usher syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Apr 08, 2021

The filtering allele frequency of the p.Ala2774Thr variant in the USH2A gene is 0.13% for European Finnish chromosome by gnomAD (35/25118), and one homozygous European (Finnish) individual and one homozygous European (non-Finnish) individual (BS1_Supporting). The REVEL computational prediction analysis tool predicted a score of 0.052, which meets the threshold to apply BP4. In summary, the HL EP classified this variant as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.056

DANN

Benign

0.66

DEOGEN2

Benign

0.015

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.25

M_CAP

Benign

0.041

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

PrimateAI

Benign

0.24

PROVEAN

Benign

0.41

REVEL

Benign

0.052

Sift

Benign

0.39

Sift4G

Benign

0.41

Polyphen

0.039

Vest4

0.084

MVP

0.71

MPC

0.030

ClinPred

0.0088

GERP RS

0.59

Varity_R

0.027

gMVP

0.24

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