rs12118814

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_StrongBS1BS2

The NM_206933.4(USH2A):c.8624G>A(p.Arg2875Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,613,608 control chromosomes in the GnomAD database, including 1,038 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2875G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.030 ( 89 hom., cov: 32)

Exomes 𝑓: 0.033 ( 949 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.72

Publications

19 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=0.0052286685).

BP6

Variant 1-215877815-C-T is Benign according to our data. Variant chr1-215877815-C-T is described in ClinVar as Benign. ClinVar VariationId is 48606.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 = 0.03 (4560/152086) while in subpopulation NFE AF = 0.0342 (2325/67988). AF 95% confidence interval is 0.033. There are 89 homozygotes in GnomAd4. There are 2274 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 89 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.8624G>A	p.Arg2875Gln	missense	Exon 43 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.8624G>A	p.Arg2875Gln	missense	Exon 43 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.8624G>A	p.Arg2875Gln	missense	Exon 43 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0300

AC:

4552

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0216

Gnomad AMI

AF:

0.0165

Gnomad AMR

AF:

0.0289

Gnomad ASJ

AF:

0.0523

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.0566

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0342

Gnomad OTH

AF:

0.0340

GnomAD2 exomes

AF:

0.0297

AC:

7463

AN:

251252

AF XY:

0.0296

show subpopulations

Gnomad AFR exome

AF:

0.0208

Gnomad AMR exome

AF:

0.0208

Gnomad ASJ exome

AF:

0.0512

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.0591

Gnomad NFE exome

AF:

0.0375

Gnomad OTH exome

AF:

0.0362

GnomAD4 exome

AF:

0.0328

AC:

47933

AN:

1461522

Hom.:

949

Cov.:

AF XY:

0.0322

AC XY:

23414

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.0228

AC:

763

AN:

33472

American (AMR)

AF:

0.0216

AC:

967

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0513

AC:

1340

AN:

26126

East Asian (EAS)

AF:

0.000403

AC:

AN:

39684

South Asian (SAS)

AF:

0.00429

AC:

370

AN:

86250

European-Finnish (FIN)

AF:

0.0587

AC:

3136

AN:

53402

Middle Eastern (MID)

AF:

0.0290

AC:

167

AN:

5768

European-Non Finnish (NFE)

AF:

0.0353

AC:

39242

AN:

1111716

Other (OTH)

AF:

0.0320

AC:

1932

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

2624

5248

7872

10496

13120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1464

2928

4392

5856

7320

<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:

0.0300

AC:

4560

AN:

152086

Hom.:

Cov.:

AF XY:

0.0306

AC XY:

2274

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0217

AC:

901

AN:

41496

American (AMR)

AF:

0.0288

AC:

440

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.0523

AC:

181

AN:

3464

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.00394

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0566

AC:

599

AN:

10576

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0342

AC:

2325

AN:

67988

Other (OTH)

AF:

0.0336

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

225

450

676

901

1126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0323

Hom.:

189

Bravo

AF:

0.0288

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0317

AC:

122

ESP6500AA

AF:

0.0207

AC:

ESP6500EA

AF:

0.0351

AC:

302

ExAC

AF:

0.0296

AC:

3600

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0360

EpiControl

AF:

0.0387

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

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

0.093

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.050

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0052

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

2.7

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.32

REVEL

Benign

0.082

Sift

Benign

0.038

Sift4G

Uncertain

0.0050

Polyphen

0.028

Vest4

0.056

MPC

0.059

ClinPred

0.019

GERP RS

3.5

Varity_R

0.054

gMVP

0.30

Mutation Taster

=91/9

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