Genetic Variant PCDH15:c.-155-176949T>C (chr10-55343600-A-G) – 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.-155-176949T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 151,472 control chromosomes in the GnomAD database, including 23,534 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 0.55 ( 23534 hom., cov: 30)

Consequence

PCDH15
NM_001354404.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.50

Publications

2 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:

ENSG00000236744 (HGNC:):

ENSG00000236744 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=-0.97).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001354404.2 link	c.-155-176949T>C		intron_variant	Intron 2 of 34		NP_001341333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000613346.4 link	c.-155-176949T>C		intron_variant	Intron 2 of 5	4		ENSP00000481211.1
ENSG00000236744	ENST00000457975.2 link	n.305+22492T>C		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.551

AC:

83381

AN:

151352

Hom.:

23498

Cov.:

show subpopulations

Gnomad AFR

AF:

0.658

Gnomad AMI

AF:

0.630

Gnomad AMR

AF:

0.549

Gnomad ASJ

AF:

0.490

Gnomad EAS

AF:

0.323

Gnomad SAS

AF:

0.445

Gnomad FIN

AF:

0.515

Gnomad MID

AF:

0.401

Gnomad NFE

AF:

0.520

Gnomad OTH

AF:

0.530

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

GnomAD4 genome

AF:

0.551

AC:

83481

AN:

151472

Hom.:

23534

Cov.:

AF XY:

0.546

AC XY:

40408

AN XY:

73962

show subpopulations

African (AFR)

AF:

0.659

AC:

27215

AN:

41316

American (AMR)

AF:

0.549

AC:

8343

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

1697

AN:

3466

East Asian (EAS)

AF:

0.323

AC:

1648

AN:

5104

South Asian (SAS)

AF:

0.444

AC:

2135

AN:

4812

European-Finnish (FIN)

AF:

0.515

AC:

5354

AN:

10394

Middle Eastern (MID)

AF:

0.397

AC:

115

AN:

290

European-Non Finnish (NFE)

AF:

0.520

AC:

35277

AN:

67882

Other (OTH)

AF:

0.532

AC:

1124

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1802

3603

5405

7206

9008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

708

1416

2124

2832

3540

<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:

0.550

Hom.:

3103

Bravo

AF:

0.559

Asia WGS

AF:

0.425

AC:

1478

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.22

(source)

DANN

Benign

0.78

PhyloP100

-1.5

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