rs41303287

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_206933.4(USH2A):c.5975A>G(p.Tyr1992Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,614,022 control chromosomes in the GnomAD database, including 15 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y1992Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 14 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:14

Conservation

PhyloP100: 3.39

Publications

14 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011217147).

BP6

Variant 1-216070175-T-C is Benign according to our data. Variant chr1-216070175-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48547.

BS2

High Homozygotes in GnomAdExome4 at 14 Unknown,AR,AD 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.5975A>G	p.Tyr1992Cys	missense	Exon 30 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.5975A>G	p.Tyr1992Cys	missense	Exon 30 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.5975A>G	p.Tyr1992Cys	missense	Exon 30 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00331

AC:

504

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0109

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00456

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00343

AC:

861

AN:

251260

AF XY:

0.00318

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000637

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0121

Gnomad NFE exome

AF:

0.00465

Gnomad OTH exome

AF:

0.00441

GnomAD4 exome

AF:

0.00383

AC:

5597

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

2682

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33470

American (AMR)

AF:

0.000760

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000209

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0104

AC:

553

AN:

53392

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00430

AC:

4779

AN:

1111934

Other (OTH)

AF:

0.00326

AC:

197

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

325

650

975

1300

1625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

360

540

720

900

<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:

0.00330

AC:

503

AN:

152282

Hom.:

Cov.:

AF XY:

0.00345

AC XY:

257

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000914

AC:

AN:

41570

American (AMR)

AF:

0.00229

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0109

AC:

116

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00454

AC:

309

AN:

68002

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00307

Hom.:

Bravo

AF:

0.00281

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00349

AC:

424

EpiCase

AF:

0.00316

EpiControl

AF:

0.00367

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (4)

Usher syndrome type 2A (2)

Progressive cone dystrophy (without rod involvement) (1)

USH2A-related disorder (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.30

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.8

PhyloP100

3.4

PrimateAI

Benign

0.33

PROVEAN

Pathogenic

-5.4

REVEL

Benign

0.25

Sift

Uncertain

0.014

Sift4G

Uncertain

0.0040

Polyphen

0.27

Vest4

0.49

MVP

0.89

MPC

0.15

ClinPred

0.072

GERP RS

2.0

Varity_R

0.27

gMVP

0.78

Mutation Taster

=77/23

polymorphism

(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