rs34596189

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_StrongBP6BS2_Supporting

The NM_206933.4(USH2A):c.3395G>A(p.Gly1132Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000371 in 1,613,854 control chromosomes in the GnomAD database, including 2 homozygotes. 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. G1132G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 2 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:8

Conservation

PhyloP100: 4.65

Publications

7 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-AS1 (HGNC:40606): (USH2A antisense RNA 1)

USH2A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.014531106).

BP6

Variant 1-216200043-C-T is Benign according to our data. Variant chr1-216200043-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166511.

BS2

High Homozygotes in GnomAdExome4 at 2 Unknown,AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3395G>A	p.Gly1132Asp	missense	Exon 17 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.3395G>A	p.Gly1132Asp	missense	Exon 17 of 21	NP_009054.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USH2A	ENST00000307340.8	TSL:1 MANE Select	c.3395G>A	p.Gly1132Asp	missense	Exon 17 of 72	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3	TSL:1	c.3395G>A	p.Gly1132Asp	missense	Exon 17 of 21	ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1		c.3395G>A	p.Gly1132Asp	missense	Exon 17 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

304

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00684

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000494

AC:

124

AN:

251128

AF XY:

0.000405

show subpopulations

Gnomad AFR exome

AF:

0.00646

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000202

AC:

295

AN:

1461804

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

123

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00708

AC:

237

AN:

33480

American (AMR)

AF:

0.000402

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111958

Other (OTH)

AF:

0.000364

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

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:

0.00199

AC:

303

AN:

152050

Hom.:

Cov.:

AF XY:

0.00198

AC XY:

147

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00680

AC:

282

AN:

41474

American (AMR)

AF:

0.000655

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10536

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

67994

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000804

Hom.:

Bravo

AF:

0.00220

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000634

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

Usher syndrome type 2A (2)

Retinitis pigmentosa (1)

USH2A-related disorder (1)

Usher syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

3.2

PhyloP100

4.6

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.57

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.72

MVP

0.94

MPC

0.25

ClinPred

0.086

GERP RS

6.0

Varity_R

0.36

gMVP

0.76

Mutation Taster

=48/52

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

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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