Genetic Variant PCDH15:c.3501+777C>A (chr10-53902466-G-T) – 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.3501+777C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 152,032 control chromosomes in the GnomAD database, including 5,899 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 0.23 ( 5899 hom., cov: 32)

Consequence

PCDH15
NM_033056.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00200

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:

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=-0.92).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.3501+777C>A		intron_variant	Intron 26 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1 link	c.3501+777C>A		intron_variant	Intron 26 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.3501+777C>A		intron_variant	Intron 26 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2 link	c.3501+777C>A		intron_variant	Intron 26 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34291

AN:

151914

Hom.:

5890

Cov.:

show subpopulations

Gnomad AFR

AF:

0.473

Gnomad AMI

AF:

0.144

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.127

Gnomad EAS

AF:

0.356

Gnomad SAS

AF:

0.217

Gnomad FIN

AF:

0.109

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.205

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

GnomAD4 genome

AF:

0.226

AC:

34349

AN:

152032

Hom.:

5899

Cov.:

AF XY:

0.226

AC XY:

16816

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.473

AC:

19617

AN:

41442

American (AMR)

AF:

0.170

AC:

2595

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

440

AN:

3464

East Asian (EAS)

AF:

0.356

AC:

1836

AN:

5162

South Asian (SAS)

AF:

0.217

AC:

1046

AN:

4820

European-Finnish (FIN)

AF:

0.109

AC:

1158

AN:

10602

Middle Eastern (MID)

AF:

0.167

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.104

AC:

7035

AN:

67964

Other (OTH)

AF:

0.210

AC:

442

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1132

2264

3395

4527

5659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

334

668

1002

1336

1670

<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:

0.138

Hom.:

1195

Bravo

AF:

0.240

Asia WGS

AF:

0.341

AC:

1181

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

3.8

(source)

DANN

Benign

0.64

PhyloP100

0.0020

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