1-215817137-C-T

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.9430G>A(p.Asp3144Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,612,664 control chromosomes in the GnomAD database, including 773 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 96 hom., cov: 32)

Exomes 𝑓: 0.028 ( 677 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.34

Publications

10 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 1 benign, 12 uncertain in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0061059594).

BP6

Variant 1-215817137-C-T is Benign according to our data. Variant chr1-215817137-C-T is described in ClinVar as Benign. ClinVar VariationId is 48627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.9430G>A	p.Asp3144Asn	missense_variant	Exon 48 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.9430G>A	p.Asp3144Asn	missense_variant	Exon 48 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.9430G>A	p.Asp3144Asn	missense_variant	Exon 48 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0338

AC:

5133

AN:

151854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0499

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0359

Gnomad ASJ

AF:

0.0398

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0258

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0287

Gnomad OTH

AF:

0.0446

GnomAD2 exomes

AF:

0.0260

AC:

6499

AN:

250212

AF XY:

0.0257

show subpopulations

Gnomad AFR exome

AF:

0.0510

Gnomad AMR exome

AF:

0.0248

Gnomad ASJ exome

AF:

0.0383

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0274

Gnomad NFE exome

AF:

0.0311

Gnomad OTH exome

AF:

0.0334

GnomAD4 exome

AF:

0.0284

AC:

41486

AN:

1460694

Hom.:

677

Cov.:

AF XY:

0.0279

AC XY:

20263

AN XY:

726656

show subpopulations

African (AFR)

AF:

0.0527

AC:

1761

AN:

33424

American (AMR)

AF:

0.0263

AC:

1174

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.0398

AC:

1037

AN:

26080

East Asian (EAS)

AF:

0.000101

AC:

AN:

39672

South Asian (SAS)

AF:

0.00348

AC:

300

AN:

86240

European-Finnish (FIN)

AF:

0.0274

AC:

1465

AN:

53410

Middle Eastern (MID)

AF:

0.0378

AC:

218

AN:

5760

European-Non Finnish (NFE)

AF:

0.0303

AC:

33629

AN:

1111096

Other (OTH)

AF:

0.0315

AC:

1898

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

2188

4375

6563

8750

10938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1286

2572

3858

5144

6430

<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:

0.0339

AC:

5146

AN:

151970

Hom.:

Cov.:

AF XY:

0.0336

AC XY:

2494

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.0501

AC:

2078

AN:

41516

American (AMR)

AF:

0.0359

AC:

545

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.0398

AC:

138

AN:

3464

East Asian (EAS)

AF:

0.000388

AC:

AN:

5150

South Asian (SAS)

AF:

0.00270

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0258

AC:

273

AN:

10592

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0287

AC:

1948

AN:

67918

Other (OTH)

AF:

0.0446

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

247

494

742

989

1236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0301

Hom.:

264

Bravo

AF:

0.0376

TwinsUK

AF:

0.0251

AC:

ALSPAC

AF:

0.0309

AC:

119

ESP6500AA

AF:

0.0522

AC:

230

ESP6500EA

AF:

0.0301

AC:

259

ExAC

AF:

0.0265

AC:

3212

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0297

EpiControl

AF:

0.0352

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 11, 2019

Athena Diagnostics

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A

Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 07, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.013

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.2

PhyloP100

2.3

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.9

REVEL

Benign

0.11

Sift

Uncertain

0.016

Sift4G

Uncertain

0.022

Polyphen

0.022

Vest4

0.054

MPC

0.033

ClinPred

0.017

GERP RS

4.3

Varity_R

0.15

gMVP

0.35

Mutation Taster

=88/12

polymorphism (auto)

(source)

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

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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