rs6657250

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.6317T>C(p.Ile2106Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 1,612,566 control chromosomes in the GnomAD database, including 346,400 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 0.67 ( 34553 hom., cov: 30)

Exomes 𝑓: 0.65 ( 311847 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.26

Publications

52 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, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Usher syndrome type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.5621682E-6).

BP6

Variant 1-216046439-A-G is Benign according to our data. Variant chr1-216046439-A-G is described in ClinVar as Benign. ClinVar VariationId is 167815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.758 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.6317T>C	p.Ile2106Thr	missense	Exon 32 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.6317T>C	p.Ile2106Thr	missense	Exon 32 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.6317T>C	p.Ile2106Thr	missense	Exon 32 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.667

AC:

101217

AN:

151670

Hom.:

34516

Cov.:

show subpopulations

Gnomad AFR

AF:

0.765

Gnomad AMI

AF:

0.667

Gnomad AMR

AF:

0.506

Gnomad ASJ

AF:

0.679

Gnomad EAS

AF:

0.445

Gnomad SAS

AF:

0.501

Gnomad FIN

AF:

0.647

Gnomad MID

AF:

0.677

Gnomad NFE

AF:

0.676

Gnomad OTH

AF:

0.653

GnomAD2 exomes

AF:

0.594

AC:

149206

AN:

251068

AF XY:

0.598

show subpopulations

Gnomad AFR exome

AF:

0.771

Gnomad AMR exome

AF:

0.353

Gnomad ASJ exome

AF:

0.680

Gnomad EAS exome

AF:

0.441

Gnomad FIN exome

AF:

0.648

Gnomad NFE exome

AF:

0.671

Gnomad OTH exome

AF:

0.625

GnomAD4 exome

AF:

0.649

AC:

947361

AN:

1460778

Hom.:

311847

Cov.:

AF XY:

0.645

AC XY:

469052

AN XY:

726748

show subpopulations

African (AFR)

AF:

0.771

AC:

25791

AN:

33446

American (AMR)

AF:

0.369

AC:

16475

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.678

AC:

17695

AN:

26104

East Asian (EAS)

AF:

0.444

AC:

17616

AN:

39678

South Asian (SAS)

AF:

0.510

AC:

44012

AN:

86234

European-Finnish (FIN)

AF:

0.653

AC:

34874

AN:

53390

Middle Eastern (MID)

AF:

0.637

AC:

3663

AN:

5752

European-Non Finnish (NFE)

AF:

0.673

AC:

748014

AN:

1111134

Other (OTH)

AF:

0.650

AC:

39221

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

17175

34350

51525

68700

85875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19162

38324

57486

76648

95810

<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:

0.667

AC:

101298

AN:

151788

Hom.:

34553

Cov.:

AF XY:

0.659

AC XY:

48880

AN XY:

74168

show subpopulations

African (AFR)

AF:

0.766

AC:

31707

AN:

41418

American (AMR)

AF:

0.505

AC:

7704

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.679

AC:

2352

AN:

3466

East Asian (EAS)

AF:

0.445

AC:

2279

AN:

5120

South Asian (SAS)

AF:

0.500

AC:

2404

AN:

4806

European-Finnish (FIN)

AF:

0.647

AC:

6821

AN:

10548

Middle Eastern (MID)

AF:

0.653

AC:

192

AN:

294

European-Non Finnish (NFE)

AF:

0.676

AC:

45865

AN:

67880

Other (OTH)

AF:

0.651

AC:

1368

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1609

3218

4826

6435

8044

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

788

1576

2364

3152

3940

<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:

0.663

Hom.:

152543

Bravo

AF:

0.657

TwinsUK

AF:

0.680

AC:

2523

ALSPAC

AF:

0.667

AC:

2569

ESP6500AA

AF:

0.761

AC:

3352

ESP6500EA

AF:

0.670

AC:

5758

ExAC

AF:

0.607

AC:

73632

Asia WGS

AF:

0.517

AC:

1800

AN:

3478

EpiCase

AF:

0.672

EpiControl

AF:

0.676

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Usher syndrome type 2A (3)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.029

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.12

MetaRNN

Benign

0.0000026

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.9

PhyloP100

1.3

PrimateAI

Benign

0.27

PROVEAN

Benign

2.0

REVEL

Benign

0.13

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.021

MPC

0.034

ClinPred

0.0022

GERP RS

5.4

Varity_R

0.029

gMVP

0.17

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