Genetic Variant NM_206933.4:c.652-13940G>A (chr1-216379025-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_206933.4(USH2A):c.652-13940G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 152,110 control chromosomes in the GnomAD database, including 2,829 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 2829 hom., cov: 32)

Consequence

USH2A
NM_206933.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.209

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 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.652-13940G>A		intron_variant	Intron 3 of 71	ENST00000307340.8	NP_996816.3	O75445-1
USH2A	NM_007123.6 link	c.652-13940G>A		intron_variant	Intron 3 of 20		NP_009054.6	O75445-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
USH2A	ENST00000307340.8 link	c.652-13940G>A	intron_variant	Intron 3 of 71	1	NM_206933.4	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3 link	c.652-13940G>A	intron_variant	Intron 3 of 20	1		ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1 link	c.652-13940G>A	intron_variant	Intron 3 of 72			ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.112

AC:

17027

AN:

151992

Hom.:

2817

Cov.:

show subpopulations

Gnomad AFR

AF:

0.360

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0532

Gnomad ASJ

AF:

0.0418

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.0605

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.0684

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.112

AC:

17068

AN:

152110

Hom.:

2829

Cov.:

AF XY:

0.110

AC XY:

8143

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.360

AC:

14918

AN:

41410

American (AMR)

AF:

0.0531

AC:

812

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0418

AC:

145

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00498

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00612

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0651

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0135

AC:

921

AN:

68014

Other (OTH)

AF:

0.0677

AC:

143

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

571

1142

1714

2285

2856

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.0358

Hom.:

1593

Bravo

AF:

0.127

Asia WGS

AF:

0.0330

AC:

114

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

5.8

(source)

DANN

Benign

0.24

PhyloP100

0.21

Mutation Taster

=100/0

polymorphism (auto)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over