1-216073261-C-T

Variant names:

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.5612G>A	p.Gly1871Asp	missense_variant	Exon 28 of 72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A-AS2	NR_125992.1 link	n.136+661C>T		intron_variant	Intron 1 of 2
USH2A-AS2	NR_125993.1 link	n.136+661C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.5612G>A	p.Gly1871Asp	missense_variant	Exon 28 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 13, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed with a second USH2A variant (phase unknown) in a patient with retinitis pigmentosa and in an unrelated patient with hearing loss in published literature (PMID: 30902645, 34837038); Observed in the heterozygous state with no other variant in the USH2A gene in a patient with retinitis pigmentosa in published literature; patient also harbored a variant in the EYS gene (PMID: 26806561); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34837038, 34426522, 32483926, 26806561, 30902645, 33623043) -

Aug 25, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Oct 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gly1871Asp in exon 28 of USH2A: This variant is not expected to have clinical significance because it has been identified in 0.3% (36/10338) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140895792). -

Jul 31, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: USH2A c.5612G>A (p.Gly1871Asp) results in a non-conservative amino acid change located in the Laminin G (IPR001791) and Fibronectin type III (IPR003961) domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 250594 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00035 vs 0.011), allowing no conclusion about variant significance. c.5612G>A has been reported in the literature in individuals affected with hearing loss and retinitis pigmentosa (examples: Perez-Carro_2015, Martin-Merida_2019, Adeyemo_2022). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34837038, 33623043, 30902645, 26806561). ClinVar contains an entry for this variant (Variation ID: 48537). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Retinitis pigmentosa 39

Pathogenic:1

Jun 23, 2021

DBGen Ocular Genomics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Childhood onset hearing loss

Uncertain:1

Jul 08, 2021

National Institute on Deafness and Communication Disorders, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

PP3 (non REVEL) / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging. -

Usher syndrome type 2A

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

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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