dbSNP rs56053654: USH2A:p.Glu3912Glu (chr1-215728360-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_206933.4(USH2A):c.11736G>A(p.Glu3912Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00838 in 1,614,108 control chromosomes in the GnomAD database, including 733 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 386 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 347 hom. )

Consequence

USH2A
NM_206933.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0410

Publications

2 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 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Usher syndrome type 2
Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 1-215728360-C-T is Benign according to our data. Variant chr1-215728360-C-T is described in ClinVar as Benign. ClinVar VariationId is 48381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.041 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

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.11736G>A	p.Glu3912Glu	synonymous	Exon 61 of 72	NP_996816.3	O75445-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.11736G>A	p.Glu3912Glu	synonymous	Exon 61 of 72	ENSP00000305941.3	O75445-1
	USH2A	ENST00000674083.1		c.11736G>A	p.Glu3912Glu	synonymous	Exon 61 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0406

AC:

6173

AN:

152160

Hom.:

387

Cov.:

show subpopulations

Gnomad AFR

AF:

0.135

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0245

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.0378

GnomAD2 exomes

AF:

0.0122

AC:

3029

AN:

248804

AF XY:

0.00929

show subpopulations

Gnomad AFR exome

AF:

0.138

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00151

Gnomad OTH exome

AF:

0.00917

GnomAD4 exome

AF:

0.00503

AC:

7353

AN:

1461830

Hom.:

347

Cov.:

AF XY:

0.00448

AC XY:

3259

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.137

AC:

4573

AN:

33476

American (AMR)

AF:

0.0125

AC:

559

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0119

AC:

312

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00230

AC:

198

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.0144

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000795

AC:

884

AN:

1112002

Other (OTH)

AF:

0.0122

AC:

739

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

402

804

1206

1608

2010

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<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:

0.0406

AC:

6176

AN:

152278

Hom.:

386

Cov.:

AF XY:

0.0385

AC XY:

2866

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.134

AC:

5576

AN:

41528

American (AMR)

AF:

0.0244

AC:

373

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00290

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00119

AC:

AN:

68030

Other (OTH)

AF:

0.0374

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

264

527

791

1054

1318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0187

Hom.:

Bravo

AF:

0.0470

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00178

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Usher syndrome type 2A (2)

Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

5.0

(source)

DANN

Benign

0.64

PhyloP100

-0.041

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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