rs41277200

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2886P) has been classified as Uncertain significance.

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

Publications

30 publications found

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 Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 39
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

USH2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain 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 Benign/Likely_benign. ClinVar VariationId is 48607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.8656C>T	p.Leu2886Phe	missense_variant	Exon 43 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.8656C>T	p.Leu2886Phe	missense_variant	Exon 43 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1 link	c.8656C>T	p.Leu2886Phe	missense_variant	Exon 43 of 73			ENSP00000501296.1

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

GnomAD2 exomes

AF:

0.0523

AC:

13130

AN:

251254

AF XY:

0.0516

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 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

African (AFR)

AF:

0.0593

AC:

1984

AN:

33464

American (AMR)

AF:

0.0622

AC:

2782

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

276

AN:

26126

East Asian (EAS)

AF:

0.135

AC:

5347

AN:

39682

South Asian (SAS)

AF:

0.0787

AC:

6789

AN:

86254

European-Finnish (FIN)

AF:

0.00889

AC:

475

AN:

53404

Middle Eastern (MID)

AF:

0.0331

AC:

191

AN:

5766

European-Non Finnish (NFE)

AF:

0.0451

AC:

50167

AN:

1111638

Other (OTH)

AF:

0.0574

AC:

3463

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

3806

7612

11417

15223

19029

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2082

4164

6246

8328

10410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0495

AC:

7532

AN:

152114

Hom.:

221

Cov.:

AF XY:

0.0501

AC XY:

3723

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0587

AC:

2437

AN:

41492

American (AMR)

AF:

0.0630

AC:

962

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3470

East Asian (EAS)

AF:

0.142

AC:

736

AN:

5178

South Asian (SAS)

AF:

0.0757

AC:

365

AN:

4822

European-Finnish (FIN)

AF:

0.00605

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0411

AC:

2793

AN:

67990

Other (OTH)

AF:

0.0522

AC:

110

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

358

716

1074

1432

1790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0446

Hom.:

620

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

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19737284, 21569298, 25528277, 17085681, 18273898, 30245029) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Jun 24, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 15, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Benign:1

Jan 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

(source)

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

PhyloP100

6.8

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

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over