1-215728281-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_206933.4(USH2A):c.11815G>A(p.Glu3939Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000397 in 1,614,098 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E3939V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:2

Conservation

PhyloP100: 3.96

Publications

10 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: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.15344846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.11815G>A	p.Glu3939Lys	missense_variant	Exon 61 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.11815G>A	p.Glu3939Lys	missense_variant	Exon 61 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.11815G>A	p.Glu3939Lys	missense_variant	Exon 61 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000492

AC:

123

AN:

250102

AF XY:

0.000539

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000827

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000392

AC:

573

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000406

AC XY:

295

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000957

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000301

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000418

AC:

465

AN:

1112006

Other (OTH)

AF:

0.000563

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

107

142

178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000447

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41540

American (AMR)

AF:

0.000589

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000750

AC:

AN:

68012

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000598

Hom.:

Bravo

AF:

0.000423

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000576

AC:

EpiCase

AF:

0.00153

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

USH2A: BP4, BS1:Supporting -

Aug 07, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported with a second variant (phase unknown) in a patient with retinitis pigmentosa in published literature (PMID: 26856745); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28224992, 22334370, 34426522, 26856745, 32707200, 35266249, 32884132, 32579692, 30718709) -

Usher syndrome type 2A

Uncertain:3

May 18, 2021

Pars Genome Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 27, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2

Mar 24, 2025

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.11815G>A (p.Glu3939Lys) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 250102 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00049 vs 0.011), allowing no conclusion about variant significance. c.11815G>A has been reported in the literature in individuals/families affected with retinitis pigmentosa and multifocal choroiditis (Neveling_2012, Tajiguli_2016, Haer-Wigman_2017, Jespersgaard_2019, McGowan_2020, Li_2021, Hufnagel_2022, Caliskan_2024) but it has also been reported in unaffected homozygous individuals (gnomAD and PMID:34426522) or individuals with unrelated conditions (PMID: 37684519), indicating it could be a benign polymorphism. In at least one of these reports, the variant was determined to not segregate in the affected family (Neveling_2012). The following publications have been ascertained in the context of this evaluation (PMID: 38576124, 28224992, 35266249, 30718709, 32707200, 32579692, 22334370, 26856745, 37684519). ClinVar contains an entry for this variant (Variation ID: 178574). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Apr 12, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Glu3939Lys va riant in USH2A has been previously reported in 4 individuals with hearing loss a nd in 3 individuals with retinitis pigmentosa (Neveling 2012, Tajiguli 2016, Hae r-Wigman 2017, LMM data); however, none of these individuals had a second pathog enic variant identified in the USH2A gene. This variant has also been identified in 0.15% (15/10150) of Ashkenazi Jewish and 0.08% (97/125366) of European chrom osomes, including one homozygote, by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org; dbSNP rs146264950). Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein. In summary, while the clinical significance of the p.Glu393 9Lys variant is uncertain, its frequency suggests that it is more likely to be b enign. ACMG/AMP Criteria applied: BS1_Supporting. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:2

May 02, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 23, 2016

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Retinitis pigmentosa 39

Uncertain:2

Nov 16, 2021

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2014

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

PhyloP100

4.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.3

REVEL

Benign

0.15

Sift

Benign

0.15

Sift4G

Pathogenic

0.0

Polyphen

0.45

Vest4

0.74

MVP

0.90

MPC

0.078

ClinPred

0.064

GERP RS

2.5

Varity_R

0.13

gMVP

0.61

Mutation Taster

=52/48

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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1-215728281-C-T

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