Genetic Variant PCDH15:c.92-8183G>A (chr10-54536060-C-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.92-8183G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 151,920 control chromosomes in the GnomAD database, including 6,759 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 0.28 ( 6759 hom., cov: 32)

Consequence

PCDH15
NM_033056.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.42

Publications

6 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:

ENSG00000234173 (HGNC:):

ENSG00000234173 links:

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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=-0.98).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.92-8183G>A		intron_variant	Intron 2 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1 link	c.92-8183G>A		intron_variant	Intron 2 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.92-8183G>A		intron_variant	Intron 2 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2 link	c.92-8183G>A		intron_variant	Intron 2 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes

AF:

0.283

AC:

42966

AN:

151802

Hom.:

6746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.407

Gnomad AMI

AF:

0.139

Gnomad AMR

AF:

0.264

Gnomad ASJ

AF:

0.192

Gnomad EAS

AF:

0.438

Gnomad SAS

AF:

0.291

Gnomad FIN

AF:

0.234

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.214

Gnomad OTH

AF:

0.258

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

GnomAD4 genome

AF:

0.283

AC:

43007

AN:

151920

Hom.:

6759

Cov.:

AF XY:

0.284

AC XY:

21067

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.408

AC:

16875

AN:

41410

American (AMR)

AF:

0.264

AC:

4028

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

665

AN:

3466

East Asian (EAS)

AF:

0.437

AC:

2254

AN:

5158

South Asian (SAS)

AF:

0.293

AC:

1406

AN:

4804

European-Finnish (FIN)

AF:

0.234

AC:

2467

AN:

10536

Middle Eastern (MID)

AF:

0.272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.214

AC:

14564

AN:

67970

Other (OTH)

AF:

0.256

AC:

541

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1508

3016

4524

6032

7540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<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:

0.238

Hom.:

19248

Bravo

AF:

0.293

Asia WGS

AF:

0.344

AC:

1195

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.17

(source)

DANN

Benign

0.21

PhyloP100

-1.4

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