NM_206933.4:c.9296A>G

Variant names:

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.9296A>G(p.Asn3099Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0302 in 1,613,804 control chromosomes in the GnomAD database, including 883 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 145 hom., cov: 32)

Exomes 𝑓: 0.029 ( 738 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.10

Publications

12 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=0.0027686954).

BP6

Variant 1-215838066-T-C is Benign according to our data. Variant chr1-215838066-T-C is described in ClinVar as Benign. ClinVar VariationId is 48620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0669 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.9296A>G	p.Asn3099Ser	missense	Exon 47 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.9296A>G	p.Asn3099Ser	missense	Exon 47 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.9296A>G	p.Asn3099Ser	missense	Exon 47 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0395

AC:

6013

AN:

152120

Hom.:

142

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0688

Gnomad AMI

AF:

0.0462

Gnomad AMR

AF:

0.0388

Gnomad ASJ

AF:

0.0413

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0262

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0290

Gnomad OTH

AF:

0.0489

GnomAD2 exomes

AF:

0.0276

AC:

6943

AN:

251320

AF XY:

0.0269

show subpopulations

Gnomad AFR exome

AF:

0.0689

Gnomad AMR exome

AF:

0.0261

Gnomad ASJ exome

AF:

0.0405

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0273

Gnomad NFE exome

AF:

0.0314

Gnomad OTH exome

AF:

0.0346

GnomAD4 exome

AF:

0.0292

AC:

42658

AN:

1461566

Hom.:

738

Cov.:

AF XY:

0.0286

AC XY:

20798

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.0746

AC:

2498

AN:

33468

American (AMR)

AF:

0.0277

AC:

1239

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0420

AC:

1097

AN:

26128

East Asian (EAS)

AF:

0.000101

AC:

AN:

39668

South Asian (SAS)

AF:

0.00365

AC:

315

AN:

86254

European-Finnish (FIN)

AF:

0.0275

AC:

1470

AN:

53414

Middle Eastern (MID)

AF:

0.0400

AC:

231

AN:

5768

European-Non Finnish (NFE)

AF:

0.0304

AC:

33804

AN:

1111764

Other (OTH)

AF:

0.0331

AC:

2000

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

2042

4083

6125

8166

10208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1304

2608

3912

5216

6520

<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:

0.0396

AC:

6028

AN:

152238

Hom.:

145

Cov.:

AF XY:

0.0392

AC XY:

2915

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0690

AC:

2867

AN:

41572

American (AMR)

AF:

0.0388

AC:

591

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.0413

AC:

143

AN:

3466

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00352

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0262

AC:

278

AN:

10618

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0290

AC:

1972

AN:

68010

Other (OTH)

AF:

0.0488

AC:

103

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

275

551

826

1102

1377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0320

Hom.:

327

Bravo

AF:

0.0436

TwinsUK

AF:

0.0256

AC:

ALSPAC

AF:

0.0309

AC:

119

ESP6500AA

AF:

0.0697

AC:

307

ESP6500EA

AF:

0.0305

AC:

262

ExAC

AF:

0.0283

AC:

3432

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0303

EpiControl

AF:

0.0356

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (4)

Usher syndrome type 2A (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

4.1

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.085

Sift

Benign

0.050

Sift4G

Uncertain

0.011

Polyphen

0.18

Vest4

0.13

MPC

0.033

ClinPred

0.021

GERP RS

2.6

Varity_R

0.089

gMVP

0.34

Mutation Taster

=51/49

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