chr1-216247094-TC-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS2_Supporting

The NM_206933.4(USH2A):c.2299delG(p.Glu767SerfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000947 in 1,613,920 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00099 ( 2 hom. )

Consequence

USH2A
NM_206933.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:55O:2

Conservation

PhyloP100: 1.75

Publications

183 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: Pathogenic. The variant received 15 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 1-216247094-TC-T is Pathogenic according to our data. Variant chr1-216247094-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.2299delG	p.Glu767SerfsTer21	frameshift	Exon 13 of 72	NP_996816.3
	USH2A	NM_007123.6		c.2299delG	p.Glu767SerfsTer21	frameshift	Exon 13 of 21	NP_009054.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USH2A	ENST00000307340.8	TSL:1 MANE Select	c.2299delG	p.Glu767SerfsTer21	frameshift	Exon 13 of 72	ENSP00000305941.3
USH2A	ENST00000366942.3	TSL:1	c.2299delG	p.Glu767SerfsTer21	frameshift	Exon 13 of 21	ENSP00000355909.3
USH2A	ENST00000674083.1		c.2299delG	p.Glu767SerfsTer21	frameshift	Exon 13 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes

AF:

0.000500

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000757

AC:

190

AN:

250832

AF XY:

0.000723

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000998

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.000994

AC:

1453

AN:

1461798

Hom.:

Cov.:

AF XY:

0.000952

AC XY:

692

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33476

American (AMR)

AF:

0.00165

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00119

AC:

1328

AN:

1111940

Other (OTH)

AF:

0.000662

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

104

208

312

416

520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.000500

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41438

American (AMR)

AF:

0.000655

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68018

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.000582

Hom.:

Bravo

AF:

0.000706

EpiCase

AF:

0.00109

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Usher syndrome type 2A (14)

not provided (12)

Retinitis pigmentosa 39 (7)

Usher syndrome (4)

Retinal dystrophy (3)

Retinitis pigmentosa (4)

USH2A-related disorder (4)

Cone-rod dystrophy (1)

Congenital stationary night blindness (1)

Inborn genetic diseases (1)

Macular dystrophy (1)

Monogenic hearing loss (1)

not specified (1)

Usher syndrome type 2 (1)

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over