chr1-215877783-G-A

Position:

chr1-215877783-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.8656C>T(p.Leu2886Phe) variant causes a missense change. The variant allele was found at a frequency of 0.049 in 1,613,538 control chromosomes in the GnomAD database, including 2,469 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 221 hom., cov: 32)

Exomes 𝑓: 0.049 ( 2248 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 6.84

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 -18 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 NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0016551912).

BP6

Variant 1-215877783-G-A is Benign according to our data. Variant chr1-215877783-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215877783-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.134 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.8656C>T	p.Leu2886Phe	missense_variant	43/72	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.8656C>T	p.Leu2886Phe	missense_variant	43/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.8656C>T	p.Leu2886Phe	missense_variant	43/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0496

AC:

7532

AN:

151996

Hom.:

222

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0588

Gnomad AMI

AF:

0.0187

Gnomad AMR

AF:

0.0632

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.142

Gnomad SAS

AF:

0.0758

Gnomad FIN

AF:

0.00605

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0411

Gnomad OTH

AF:

0.0513

GnomAD3 exomes

AF:

0.0523

AC:

13130

AN:

251254

Hom.:

546

AF XY:

0.0516

AC XY:

7009

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.0606

Gnomad AMR exome

AF:

0.0625

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.156

Gnomad SAS exome

AF:

0.0799

Gnomad FIN exome

AF:

0.00758

Gnomad NFE exome

AF:

0.0365

Gnomad OTH exome

AF:

0.0413

GnomAD4 exome

AF:

0.0489

AC:

71474

AN:

1461424

Hom.:

2248

Cov.:

AF XY:

0.0491

AC XY:

35702

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.0593

Gnomad4 AMR exome

AF:

0.0622

Gnomad4 ASJ exome

AF:

0.0106

Gnomad4 EAS exome

AF:

0.135

Gnomad4 SAS exome

AF:

0.0787

Gnomad4 FIN exome

AF:

0.00889

Gnomad4 NFE exome

AF:

0.0451

Gnomad4 OTH exome

AF:

0.0574

GnomAD4 genome

AF:

0.0495

AC:

7532

AN:

152114

Hom.:

221

Cov.:

AF XY:

0.0501

AC XY:

3723

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0587

Gnomad4 AMR

AF:

0.0630

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.142

Gnomad4 SAS

AF:

0.0757

Gnomad4 FIN

AF:

0.00605

Gnomad4 NFE

AF:

0.0411

Gnomad4 OTH

AF:

0.0522

Alfa

AF:

0.0436

Hom.:

299

Bravo

AF:

0.0527

TwinsUK

AF:

0.0488

AC:

181

ALSPAC

AF:

0.0410

AC:

158

ESP6500AA

AF:

0.0624

AC:

275

ESP6500EA

AF:

0.0381

AC:

328

ExAC

AF:

0.0520

AC:

6309

Asia WGS

AF:

0.103

AC:

359

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	This variant is associated with the following publications: (PMID: 19737284, 21569298, 25528277, 17085681, 18273898, 30245029) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2009	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

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	Jul 01, 2021	- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 04, 2022

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.037

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.48

DEOGEN2

Benign

0.062

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.26

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

2.5

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.065

MPC

0.031

ClinPred

0.0098

GERP RS

5.9

Varity_R

0.056

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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