rs56038610

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_206933.4(USH2A):c.15091C>T(p.Arg5031Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,614,150 control chromosomes in the GnomAD database, including 343 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. R5031Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 24 hom., cov: 32)

Exomes 𝑓: 0.019 ( 319 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 3.18

Publications

17 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=0.0028478205).

BP6

Variant 1-215634665-G-A is Benign according to our data. Variant chr1-215634665-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0133 (2029/152266) while in subpopulation NFE AF = 0.0174 (1184/68026). AF 95% confidence interval is 0.0166. There are 24 homozygotes in GnomAd4. There are 1108 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AD,AR gene

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.15091C>T	p.Arg5031Trp	missense	Exon 70 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.15091C>T	p.Arg5031Trp	missense	Exon 70 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.15091C>T	p.Arg5031Trp	missense	Exon 70 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2030

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00316

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00975

Gnomad FIN

AF:

0.0555

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0174

Gnomad OTH

AF:

0.00960

GnomAD2 exomes

AF:

0.0156

AC:

3921

AN:

251424

AF XY:

0.0158

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0537

Gnomad NFE exome

AF:

0.0192

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0186

AC:

27246

AN:

1461884

Hom.:

319

Cov.:

AF XY:

0.0181

AC XY:

13147

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00251

AC:

AN:

33480

American (AMR)

AF:

0.00288

AC:

129

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0108

AC:

935

AN:

86258

European-Finnish (FIN)

AF:

0.0508

AC:

2714

AN:

53414

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0201

AC:

22391

AN:

1112008

Other (OTH)

AF:

0.0152

AC:

918

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1604

3208

4812

6416

8020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

850

1700

2550

3400

4250

<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:

0.0133

AC:

2029

AN:

152266

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1108

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00315

AC:

131

AN:

41566

American (AMR)

AF:

0.00334

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00976

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0555

AC:

588

AN:

10600

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0174

AC:

1184

AN:

68026

Other (OTH)

AF:

0.00950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

107

214

321

428

535

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0156

Hom.:

Bravo

AF:

0.00952

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0244

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0174

AC:

150

ExAC

AF:

0.0157

AC:

1908

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0142

EpiControl

AF:

0.0137

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (4)

Usher syndrome type 2A (2)

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

3.2

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.55

REVEL

Benign

0.089

Sift

Benign

0.12

Sift4G

Uncertain

0.028

Polyphen

0.88

Vest4

0.084

MPC

0.067

ClinPred

0.017

GERP RS

2.9

Varity_R

0.057

gMVP

0.25

Mutation Taster

=97/3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over