rs646094

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_206933.4(USH2A):c.3812-8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,608,604 control chromosomes in the GnomAD database, including 41,222 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3260 hom., cov: 32)

Exomes 𝑓: 0.23 ( 37962 hom. )

Consequence

USH2A
NM_206933.4 splice_region, intron

Scores

Splicing: ADA: 0.002956

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.63

Publications

17 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 1-216198592-A-C is Benign according to our data. Variant chr1-216198592-A-C is described in ClinVar as [Benign]. Clinvar id is 48508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.3812-8T>G		splice_region_variant, intron_variant	Intron 17 of 71	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.3812-8T>G		splice_region_variant, intron_variant	Intron 17 of 71	1	NM_206933.4	ENSP00000305941.3		O75445-1

Frequencies

GnomAD3 genomes

AF:

0.205

AC:

31090

AN:

151976

Hom.:

3257

Cov.:

show subpopulations

Gnomad AFR

AF:

0.164

Gnomad AMI

AF:

0.138

Gnomad AMR

AF:

0.209

Gnomad ASJ

AF:

0.221

Gnomad EAS

AF:

0.220

Gnomad SAS

AF:

0.221

Gnomad FIN

AF:

0.143

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.236

Gnomad OTH

AF:

0.210

GnomAD2 exomes

AF:

0.213

AC:

52476

AN:

246022

AF XY:

0.217

show subpopulations

Gnomad AFR exome

AF:

0.164

Gnomad AMR exome

AF:

0.189

Gnomad ASJ exome

AF:

0.225

Gnomad EAS exome

AF:

0.206

Gnomad FIN exome

AF:

0.153

Gnomad NFE exome

AF:

0.234

Gnomad OTH exome

AF:

0.224

GnomAD4 exome

AF:

0.226

AC:

329796

AN:

1456510

Hom.:

37962

Cov.:

AF XY:

0.228

AC XY:

165060

AN XY:

724752

show subpopulations

African (AFR)

AF:

0.160

AC:

5361

AN:

33432

American (AMR)

AF:

0.190

AC:

8495

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.225

AC:

5885

AN:

26102

East Asian (EAS)

AF:

0.191

AC:

7555

AN:

39570

South Asian (SAS)

AF:

0.232

AC:

19996

AN:

86160

European-Finnish (FIN)

AF:

0.160

AC:

8157

AN:

51112

Middle Eastern (MID)

AF:

0.212

AC:

1206

AN:

5700

European-Non Finnish (NFE)

AF:

0.234

AC:

260021

AN:

1109570

Other (OTH)

AF:

0.218

AC:

13120

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

12102

24205

36307

48410

60512

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.204

AC:

31103

AN:

152094

Hom.:

3260

Cov.:

AF XY:

0.201

AC XY:

14917

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.164

AC:

6798

AN:

41516

American (AMR)

AF:

0.209

AC:

3187

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.221

AC:

767

AN:

3472

East Asian (EAS)

AF:

0.220

AC:

1137

AN:

5160

South Asian (SAS)

AF:

0.220

AC:

1061

AN:

4820

European-Finnish (FIN)

AF:

0.143

AC:

1508

AN:

10578

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.236

AC:

16013

AN:

67946

Other (OTH)

AF:

0.208

AC:

440

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1277

2555

3832

5110

6387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.223

Hom.:

1542

Bravo

AF:

0.204

Asia WGS

AF:

0.185

AC:

643

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 10, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A

Benign:3

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Retinitis pigmentosa

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

5.4

(source)

DANN

Benign

0.73

PhyloP100

2.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0030

dbscSNV1_RF

Benign

0.16

SpliceAI score (max)

0.14

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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rs646094

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