rs140895792

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_206933.4(USH2A):c.5612G>A(p.Gly1871Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000266 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G1871G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:3

Conservation

PhyloP100: 4.81

Publications

6 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 links:

USH2A-AS2 (HGNC:40605): (USH2A antisense RNA 2)

USH2A-AS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0653944).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USH2A	NM_206933.4	MANE Select	c.5612G>A	p.Gly1871Asp	missense	Exon 28 of 72	NP_996816.3	O75445-1
USH2A-AS2	NR_125992.1		n.136+661C>T		intron	N/A
USH2A-AS2	NR_125993.1		n.136+661C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USH2A	ENST00000307340.8	TSL:1 MANE Select	c.5612G>A	p.Gly1871Asp	missense	Exon 28 of 72	ENSP00000305941.3	O75445-1
USH2A	ENST00000674083.1		c.5612G>A	p.Gly1871Asp	missense	Exon 28 of 73	ENSP00000501296.1	O75445-3
USH2A-AS2	ENST00000430890.5	TSL:2	n.78+455C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

156

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000351

AC:

AN:

250594

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.00320

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.000795

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000186

AC:

272

AN:

1461626

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

127

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.00275

AC:

AN:

33474

American (AMR)

AF:

0.000470

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00111

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000899

AC:

100

AN:

1111912

Other (OTH)

AF:

0.000364

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00103

AC:

157

AN:

152158

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00291

AC:

121

AN:

41514

American (AMR)

AF:

0.00124

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68002

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000468

Hom.:

Bravo

AF:

0.00124

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Childhood onset hearing loss (1)

Retinitis pigmentosa 39 (1)

Usher syndrome type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.065

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

3.0

PhyloP100

4.8

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.66

Sift

Uncertain

0.010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.76

MVP

0.94

MPC

0.26

ClinPred

0.091

GERP RS

5.9

Varity_R

0.49

gMVP

0.49

Mutation Taster

=3/97

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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