NM_206933.4:c.4994T>C

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.4994T>C(p.Ile1665Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,612,682 control chromosomes in the GnomAD database, including 14,579 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.10 ( 1044 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13535 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.681

Publications

20 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 links:

USH2A-AS2 (HGNC:40605): (USH2A antisense RNA 2)

USH2A-AS2 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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0014926493).

BP6

Variant 1-216084871-A-G is Benign according to our data. Variant chr1-216084871-A-G is described in CliVar as Benign. Clinvar id is 48525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216084871-A-G is described in CliVar as Benign. Clinvar id is 48525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216084871-A-G is described in CliVar as Benign. Clinvar id is 48525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.4994T>C	p.Ile1665Thr	missense_variant	Exon 25 of 72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A-AS2	NR_125992.1 link	n.266-1851A>G		intron_variant	Intron 2 of 2
USH2A-AS2	NR_125993.1 link	n.137-1851A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.4994T>C	p.Ile1665Thr	missense_variant	Exon 25 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15330

AN:

152112

Hom.:

1044

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0256

Gnomad AMI

AF:

0.247

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.178

Gnomad EAS

AF:

0.0243

Gnomad SAS

AF:

0.0705

Gnomad FIN

AF:

0.131

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.141

Gnomad OTH

AF:

0.130

GnomAD2 exomes

AF:

0.110

AC:

27645

AN:

250302

AF XY:

0.113

show subpopulations

Gnomad AFR exome

AF:

0.0213

Gnomad AMR exome

AF:

0.0858

Gnomad ASJ exome

AF:

0.182

Gnomad EAS exome

AF:

0.0209

Gnomad FIN exome

AF:

0.130

Gnomad NFE exome

AF:

0.143

Gnomad OTH exome

AF:

0.145

GnomAD4 exome

AF:

0.131

AC:

191566

AN:

1460452

Hom.:

13535

Cov.:

AF XY:

0.130

AC XY:

94740

AN XY:

726616

show subpopulations

African (AFR)

AF:

0.0215

AC:

718

AN:

33412

American (AMR)

AF:

0.0891

AC:

3972

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.183

AC:

4766

AN:

26096

East Asian (EAS)

AF:

0.0213

AC:

844

AN:

39672

South Asian (SAS)

AF:

0.0744

AC:

6414

AN:

86238

European-Finnish (FIN)

AF:

0.132

AC:

7047

AN:

53304

Middle Eastern (MID)

AF:

0.168

AC:

966

AN:

5754

European-Non Finnish (NFE)

AF:

0.143

AC:

158971

AN:

1111068

Other (OTH)

AF:

0.130

AC:

7868

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

7947

15894

23841

31788

39735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5588

11176

16764

22352

27940

<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:

0.101

AC:

15331

AN:

152230

Hom.:

1044

Cov.:

AF XY:

0.101

AC XY:

7482

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0256

AC:

1063

AN:

41566

American (AMR)

AF:

0.108

AC:

1657

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.178

AC:

617

AN:

3470

East Asian (EAS)

AF:

0.0249

AC:

129

AN:

5180

South Asian (SAS)

AF:

0.0710

AC:

343

AN:

4830

European-Finnish (FIN)

AF:

0.131

AC:

1383

AN:

10594

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.141

AC:

9591

AN:

67982

Other (OTH)

AF:

0.129

AC:

272

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

690

1380

2070

2760

3450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

166

332

498

664

830

<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:

0.135

Hom.:

2643

Bravo

AF:

0.0974

TwinsUK

AF:

0.136

AC:

504

ALSPAC

AF:

0.144

AC:

554

ESP6500AA

AF:

0.0282

AC:

124

ESP6500EA

AF:

0.157

AC:

1354

ExAC

AF:

0.110

AC:

13301

Asia WGS

AF:

0.0610

AC:

212

AN:

3476

EpiCase

AF:

0.153

EpiControl

AF:

0.152

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 07, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

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

0.10

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

8.1

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.046

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

0.68

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.84

REVEL

Benign

0.15

Sift

Benign

0.17

Sift4G

Uncertain

0.041

Polyphen

0.0070

Vest4

0.075

MPC

0.035

ClinPred

0.0013

GERP RS

2.6

Varity_R

0.089

gMVP

0.40

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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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