Genetic Variant PCDH15:c.158-1083C>T (chr10-54380025-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_033056.4(PCDH15):c.158-1083C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.879 in 152,078 control chromosomes in the GnomAD database, including 58,764 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 0.88 ( 58764 hom., cov: 32)

Consequence

PCDH15
NM_033056.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.686

Publications

4 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=-1.0).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.158-1083C>T		intron_variant	Intron 3 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1 link	c.158-1083C>T		intron_variant	Intron 3 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 link	c.158-1083C>T		intron_variant	Intron 3 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2 link	c.158-1083C>T		intron_variant	Intron 3 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes

AF:

0.879

AC:

133501

AN:

151960

Hom.:

58714

Cov.:

show subpopulations

Gnomad AFR

AF:

0.859

Gnomad AMI

AF:

0.979

Gnomad AMR

AF:

0.910

Gnomad ASJ

AF:

0.840

Gnomad EAS

AF:

0.986

Gnomad SAS

AF:

0.831

Gnomad FIN

AF:

0.849

Gnomad MID

AF:

0.794

Gnomad NFE

AF:

0.884

Gnomad OTH

AF:

0.876

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

GnomAD4 genome

AF:

0.879

AC:

133607

AN:

152078

Hom.:

58764

Cov.:

AF XY:

0.878

AC XY:

65243

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.859

AC:

35655

AN:

41498

American (AMR)

AF:

0.910

AC:

13889

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.840

AC:

2913

AN:

3468

East Asian (EAS)

AF:

0.986

AC:

5085

AN:

5158

South Asian (SAS)

AF:

0.830

AC:

4011

AN:

4832

European-Finnish (FIN)

AF:

0.849

AC:

8992

AN:

10588

Middle Eastern (MID)

AF:

0.793

AC:

233

AN:

294

European-Non Finnish (NFE)

AF:

0.884

AC:

60084

AN:

67960

Other (OTH)

AF:

0.877

AC:

1852

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

809

1617

2426

3234

4043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

898

1796

2694

3592

4490

<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:

0.885

Hom.:

9672

Bravo

AF:

0.884

Asia WGS

AF:

0.917

AC:

3183

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.11

(source)

DANN

Benign

0.57

PhyloP100

-0.69

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