rs41315587

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.14513G>A(p.Gly4838Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,038 control chromosomes in the GnomAD database, including 450 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G4838R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.019 ( 71 hom., cov: 32)

Exomes 𝑓: 0.010 ( 379 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.908

Publications

14 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 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Usher syndrome type 2
Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024906397).

BP6

Variant 1-215648597-C-T is Benign according to our data. Variant chr1-215648597-C-T is described in ClinVar as Benign. ClinVar VariationId is 48439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0641 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206933.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.14513G>A	p.Gly4838Glu	missense	Exon 66 of 72	NP_996816.3	O75445-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.14513G>A	p.Gly4838Glu	missense	Exon 66 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.14513G>A	p.Gly4838Glu	missense	Exon 66 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0186

AC:

2835

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0456

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00923

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0297

Gnomad SAS

AF:

0.0700

Gnomad FIN

AF:

0.00434

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00353

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0155

AC:

3901

AN:

251300

AF XY:

0.0174

show subpopulations

Gnomad AFR exome

AF:

0.0471

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0188

Gnomad FIN exome

AF:

0.00300

Gnomad NFE exome

AF:

0.00386

Gnomad OTH exome

AF:

0.00962

GnomAD4 exome

AF:

0.0104

AC:

15168

AN:

1461790

Hom.:

379

Cov.:

AF XY:

0.0118

AC XY:

8580

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0472

AC:

1580

AN:

33476

American (AMR)

AF:

0.00362

AC:

162

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.0506

AC:

2008

AN:

39700

South Asian (SAS)

AF:

0.0665

AC:

5733

AN:

86240

European-Finnish (FIN)

AF:

0.00253

AC:

135

AN:

53416

Middle Eastern (MID)

AF:

0.00659

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00432

AC:

4800

AN:

1111938

Other (OTH)

AF:

0.0117

AC:

709

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

833

1666

2498

3331

4164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

278

556

834

1112

1390

<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:

0.0187

AC:

2842

AN:

152248

Hom.:

Cov.:

AF XY:

0.0194

AC XY:

1443

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0456

AC:

1896

AN:

41548

American (AMR)

AF:

0.00922

AC:

141

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.0298

AC:

154

AN:

5166

South Asian (SAS)

AF:

0.0703

AC:

339

AN:

4824

European-Finnish (FIN)

AF:

0.00434

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00353

AC:

240

AN:

68020

Other (OTH)

AF:

0.0109

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

135

271

406

542

677

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.00845

Hom.:

Bravo

AF:

0.0183

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.0472

AC:

208

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.0174

AC:

2106

Asia WGS

AF:

0.0520

AC:

182

AN:

3478

EpiCase

AF:

0.00442

EpiControl

AF:

0.00320

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Usher syndrome type 2A (2)

Retinal dystrophy (1)

Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.74

CADD

Benign

5.7

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.016

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.060

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.75

PhyloP100

0.91

PrimateAI

Benign

0.30

PROVEAN

Benign

1.4

REVEL

Benign

0.092

Sift

Benign

1.0

Sift4G

Benign

0.83

Polyphen

0.0

Vest4

0.050

MPC

0.035

ClinPred

0.0027

GERP RS

4.5

Varity_R

0.040

gMVP

0.37

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over