NM_206933.4:c.2777G>A

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.2777G>A(p.Arg926His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,613,896 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R926C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 1 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 0.693

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 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.123541355).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.2777G>A	p.Arg926His	missense	Exon 13 of 72	NP_996816.3
	USH2A	NM_007123.6		c.2777G>A	p.Arg926His	missense	Exon 13 of 21	NP_009054.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USH2A	ENST00000307340.8	TSL:1 MANE Select	c.2777G>A	p.Arg926His	missense	Exon 13 of 72	ENSP00000305941.3
USH2A	ENST00000366942.3	TSL:1	c.2777G>A	p.Arg926His	missense	Exon 13 of 21	ENSP00000355909.3
USH2A	ENST00000674083.1		c.2777G>A	p.Arg926His	missense	Exon 13 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000478

AC:

AN:

251100

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000623

AC:

AN:

1461768

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000612

AC:

AN:

1111922

Other (OTH)

AF:

0.0000994

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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:

0.0000394

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41434

American (AMR)

AF:

0.0000656

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

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:

0.0000574

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 01, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 25078356)

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 926 of the USH2A protein (p.Arg926His). This variant is present in population databases (rs146916397, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 48491). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt USH2A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Retinal dystrophy

Uncertain:2

Nov 12, 2018

Blueprint Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

not specified

Uncertain:1

Sep 17, 2011

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 Arg926His varia nt in USH2A has not been reported in the literature nor previously identified by our laboratory. Computational analyses (biochemical amino acid properties, homo logy, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or against p athogenicity. In summary, the clinical significance of this variant cannot be de termined with certainty at this time.

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1

Feb 27, 2017

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:1

Nov 04, 2023

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Usher syndrome type 2A

Uncertain:1

Nov 04, 2023

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.055

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.79

M_CAP

Benign

0.015

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.5

PhyloP100

0.69

PrimateAI

Benign

0.23

PROVEAN

Benign

-2.4

REVEL

Benign

0.089

Sift

Benign

0.041

Sift4G

Benign

0.092

Polyphen

0.51

Vest4

0.33

MVP

0.64

MPC

0.074

ClinPred

0.12

GERP RS

2.7

Varity_R

0.16

gMVP

0.60

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over