Genetic Variant USH2A:c.4759-1907T>G (chr1-216091046-A-C) – 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.4759-1907T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 151,958 control chromosomes in the GnomAD database, including 11,577 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 0.38 ( 11577 hom., cov: 32)

Consequence

USH2A
NM_206933.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.241

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=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.4759-1907T>G		intron_variant	Intron 22 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.4759-1907T>G		intron_variant	Intron 22 of 71	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.4759-1907T>G		intron_variant	Intron 22 of 72			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.376

AC:

57084

AN:

151840

Hom.:

11570

Cov.:

show subpopulations

Gnomad AFR

AF:

0.307

Gnomad AMI

AF:

0.329

Gnomad AMR

AF:

0.487

Gnomad ASJ

AF:

0.414

Gnomad EAS

AF:

0.848

Gnomad SAS

AF:

0.488

Gnomad FIN

AF:

0.396

Gnomad MID

AF:

0.325

Gnomad NFE

AF:

0.344

Gnomad OTH

AF:

0.398

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

GnomAD4 genome

AF:

0.376

AC:

57112

AN:

151958

Hom.:

11577

Cov.:

AF XY:

0.384

AC XY:

28507

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.307

AC:

12724

AN:

41460

American (AMR)

AF:

0.488

AC:

7449

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.414

AC:

1435

AN:

3468

East Asian (EAS)

AF:

0.848

AC:

4370

AN:

5154

South Asian (SAS)

AF:

0.488

AC:

2347

AN:

4814

European-Finnish (FIN)

AF:

0.396

AC:

4185

AN:

10558

Middle Eastern (MID)

AF:

0.315

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.344

AC:

23370

AN:

67928

Other (OTH)

AF:

0.399

AC:

840

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1741

3482

5224

6965

8706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

550

1100

1650

2200

2750

<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:

0.362

Hom.:

29857

Bravo

AF:

0.384

Asia WGS

AF:

0.610

AC:

2123

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.96

(source)

DANN

Benign

0.74

PhyloP100

0.24

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