1-215741541-GAA-GAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_206933.4(USH2A):c.11549-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0432 in 928,684 control chromosomes in the GnomAD database, including 2 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00094 ( 1 hom., cov: 32)

Exomes 𝑓: 0.051 ( 1 hom. )

Consequence

USH2A
NM_206933.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.396

Publications

4 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 -8 ACMG points.

BP6

Variant 1-215741541-G-GA is Benign according to our data. Variant chr1-215741541-G-GA is described in ClinVar as Benign. ClinVar VariationId is 198307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.11549-5dupT		splice_region_variant, intron_variant	Intron 59 of 71	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.11549-5_11549-4insT		splice_region_variant, intron_variant	Intron 59 of 71	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1 link	c.11549-5_11549-4insT		splice_region_variant, intron_variant	Intron 59 of 72			ENSP00000501296.1

Frequencies

GnomAD3 genomes

AF:

0.000931

AC:

129

AN:

138634

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000423

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000862

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000450

Gnomad FIN

AF:

0.00533

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000880

Gnomad OTH

AF:

0.00106

GnomAD2 exomes

AF:

0.0572

AC:

6751

AN:

118084

AF XY:

0.0557

show subpopulations

Gnomad AFR exome

AF:

0.0416

Gnomad AMR exome

AF:

0.0767

Gnomad ASJ exome

AF:

0.0900

Gnomad EAS exome

AF:

0.0598

Gnomad FIN exome

AF:

0.0596

Gnomad NFE exome

AF:

0.0481

Gnomad OTH exome

AF:

0.0741

GnomAD4 exome

AF:

0.0507

AC:

40031

AN:

789990

Hom.:

Cov.:

AF XY:

0.0506

AC XY:

19779

AN XY:

391068

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0578

AC:

1015

AN:

17546

American (AMR)

AF:

0.0643

AC:

1679

AN:

26130

Ashkenazi Jewish (ASJ)

AF:

0.0698

AC:

882

AN:

12634

East Asian (EAS)

AF:

0.0588

AC:

1227

AN:

20872

South Asian (SAS)

AF:

0.0637

AC:

2810

AN:

44120

European-Finnish (FIN)

AF:

0.0558

AC:

1666

AN:

29874

Middle Eastern (MID)

AF:

0.0354

AC:

133

AN:

3754

European-Non Finnish (NFE)

AF:

0.0479

AC:

28855

AN:

602988

Other (OTH)

AF:

0.0550

AC:

1764

AN:

32072

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.244

Heterozygous variant carriers

6590

13181

19771

26362

32952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

968

1936

2904

3872

4840

<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:

0.000937

AC:

130

AN:

138694

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

66854

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

37918

American (AMR)

AF:

0.000860

AC:

AN:

13946

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3288

East Asian (EAS)

AF:

0.00

AC:

AN:

4784

South Asian (SAS)

AF:

0.000451

AC:

AN:

4438

European-Finnish (FIN)

AF:

0.00533

AC:

AN:

7696

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.000880

AC:

AN:

63614

Other (OTH)

AF:

0.00105

AC:

AN:

1898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

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:

0.0555

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Usher syndrome type 2A

Benign:2

Sep 25, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Aug 29, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retinitis pigmentosa 39

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.40

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over