dbSNP rs11004706: PCDH15:c.-80+112667A>G (chr10-55053909-T-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_001354404.2(PCDH15):c.-80+112667A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0701 in 152,290 control chromosomes in the GnomAD database, including 574 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 0.070 ( 574 hom., cov: 32)

Consequence

PCDH15
NM_001354404.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.261

Publications

3 publications found

Variant links:

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

PCDH15 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 23
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1F
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

PCDH15 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 = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001354404.2 link	c.-80+112667A>G		intron_variant	Intron 3 of 34		NP_001341333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000458638.1 link	c.-80+112667A>G		intron_variant	Intron 2 of 5	5		ENSP00000394465.1
PCDH15	ENST00000613346.4 link	c.-80+112667A>G		intron_variant	Intron 3 of 5	4		ENSP00000481211.1

Frequencies

GnomAD3 genomes

AF:

0.0701

AC:

10662

AN:

152172

Hom.:

572

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0481

Gnomad ASJ

AF:

0.0763

Gnomad EAS

AF:

0.00404

Gnomad SAS

AF:

0.0603

Gnomad FIN

AF:

0.00969

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0493

Gnomad OTH

AF:

0.0683

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

GnomAD4 genome

AF:

0.0701

AC:

10680

AN:

152290

Hom.:

574

Cov.:

AF XY:

0.0680

AC XY:

5064

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.138

AC:

5741

AN:

41540

American (AMR)

AF:

0.0480

AC:

735

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0763

AC:

265

AN:

3472

East Asian (EAS)

AF:

0.00405

AC:

AN:

5182

South Asian (SAS)

AF:

0.0609

AC:

294

AN:

4824

European-Finnish (FIN)

AF:

0.00969

AC:

103

AN:

10626

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0493

AC:

3354

AN:

68018

Other (OTH)

AF:

0.0676

AC:

143

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

486

972

1458

1944

2430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0565

Hom.:

149

Bravo

AF:

0.0733

Asia WGS

AF:

0.0310

AC:

106

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

1.6

(source)

DANN

Benign

0.58

PhyloP100

0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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