chr1-216175422-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.4457G>A(p.Arg1486Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,613,420 control chromosomes in the GnomAD database, including 326,396 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 0.63 ( 30324 hom., cov: 32)

Exomes 𝑓: 0.63 ( 296072 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.52

Publications

55 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 Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, 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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=1.6309556E-6).

BP6

Variant 1-216175422-C-T is Benign according to our data. Variant chr1-216175422-C-T is described in ClinVar as Benign. ClinVar VariationId is 177992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.4457G>A	p.Arg1486Lys	missense_variant	Exon 21 of 72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6 link	c.4457G>A	p.Arg1486Lys	missense_variant	Exon 21 of 21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
USH2A	ENST00000307340.8 link	c.4457G>A	p.Arg1486Lys	missense_variant	Exon 21 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3 link	c.4457G>A	p.Arg1486Lys	missense_variant	Exon 21 of 21	1		ENSP00000355909.3
USH2A	ENST00000674083.1 link	c.4457G>A	p.Arg1486Lys	missense_variant	Exon 21 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes

AF:

0.629

AC:

95572

AN:

151932

Hom.:

30303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.577

Gnomad AMI

AF:

0.799

Gnomad AMR

AF:

0.661

Gnomad ASJ

AF:

0.587

Gnomad EAS

AF:

0.762

Gnomad SAS

AF:

0.709

Gnomad FIN

AF:

0.728

Gnomad MID

AF:

0.563

Gnomad NFE

AF:

0.623

Gnomad OTH

AF:

0.626

GnomAD2 exomes

AF:

0.661

AC:

165406

AN:

250414

AF XY:

0.659

show subpopulations

Gnomad AFR exome

AF:

0.581

Gnomad AMR exome

AF:

0.716

Gnomad ASJ exome

AF:

0.576

Gnomad EAS exome

AF:

0.781

Gnomad FIN exome

AF:

0.722

Gnomad NFE exome

AF:

0.623

Gnomad OTH exome

AF:

0.630

GnomAD4 exome

AF:

0.635

AC:

927401

AN:

1461370

Hom.:

296072

Cov.:

AF XY:

0.635

AC XY:

461871

AN XY:

726974

show subpopulations

African (AFR)

AF:

0.574

AC:

19199

AN:

33470

American (AMR)

AF:

0.710

AC:

31736

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.575

AC:

15019

AN:

26120

East Asian (EAS)

AF:

0.799

AC:

31656

AN:

39620

South Asian (SAS)

AF:

0.698

AC:

60164

AN:

86256

European-Finnish (FIN)

AF:

0.712

AC:

38022

AN:

53386

Middle Eastern (MID)

AF:

0.606

AC:

3491

AN:

5756

European-Non Finnish (NFE)

AF:

0.621

AC:

689907

AN:

1111728

Other (OTH)

AF:

0.633

AC:

38207

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

20446

40892

61338

81784

102230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18568

37136

55704

74272

92840

<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:

0.629

AC:

95627

AN:

152050

Hom.:

30324

Cov.:

AF XY:

0.636

AC XY:

47233

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.576

AC:

23911

AN:

41482

American (AMR)

AF:

0.662

AC:

10103

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.587

AC:

2038

AN:

3472

East Asian (EAS)

AF:

0.762

AC:

3918

AN:

5140

South Asian (SAS)

AF:

0.710

AC:

3421

AN:

4820

European-Finnish (FIN)

AF:

0.728

AC:

7699

AN:

10576

Middle Eastern (MID)

AF:

0.561

AC:

165

AN:

294

European-Non Finnish (NFE)

AF:

0.623

AC:

42324

AN:

67984

Other (OTH)

AF:

0.627

AC:

1319

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1836

3673

5509

7346

9182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

786

1572

2358

3144

3930

<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:

0.624

Hom.:

119883

Bravo

AF:

0.624

TwinsUK

AF:

0.621

AC:

2302

ALSPAC

AF:

0.625

AC:

2408

ESP6500AA

AF:

0.596

AC:

2626

ESP6500EA

AF:

0.612

AC:

5261

ExAC

AF:

0.657

AC:

79731

Asia WGS

AF:

0.731

AC:

2543

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Feb 02, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inferred frequency = 141/386 (LMM data) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 10, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A

Benign:2

Nov 18, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.63

CADD

Benign

9.8

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.021

T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

0.0000016

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

-1.5

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.16

N;N

REVEL

Benign

0.024

Sift

Benign

0.42

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.094

B;B

Vest4

0.044

MPC

0.032

ClinPred

0.0025

GERP RS

-2.2

Varity_R

0.085

gMVP

0.34

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over