10-53866870-GAA-GAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_033056.4(PCDH15):c.3502-14_3502-13insT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,477,920 control chromosomes in the GnomAD database, including 32,181 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 6332 hom., cov: 22)

Exomes 𝑓: 0.18 ( 25849 hom. )

Consequence

PCDH15
NM_033056.4 splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.936

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 10-53866870-G-GA is Benign according to our data. Variant chr10-53866870-G-GA is described in ClinVar as [Benign]. Clinvar id is 46468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1 linkuse as main transcript	c.3502-14_3502-13insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000644397.2
PCDH15	NM_033056.4 linkuse as main transcript	c.3502-14_3502-13insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000320301.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11 linkuse as main transcript	c.3502-14_3502-13insT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_033056.4		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.3502-14_3502-13insT		splice_polypyrimidine_tract_variant, intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes

AF:

0.258

AC:

38704

AN:

149830

Hom.:

6331

Cov.:

show subpopulations

Gnomad AFR

AF:

0.360

Gnomad AMI

AF:

0.234

Gnomad AMR

AF:

0.292

Gnomad ASJ

AF:

0.162

Gnomad EAS

AF:

0.756

Gnomad SAS

AF:

0.352

Gnomad FIN

AF:

0.206

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.159

Gnomad OTH

AF:

0.241

GnomAD3 exomes

AF:

0.262

AC:

60911

AN:

232130

Hom.:

8545

AF XY:

0.254

AC XY:

32017

AN XY:

125860

show subpopulations

Gnomad AFR exome

AF:

0.343

Gnomad AMR exome

AF:

0.374

Gnomad ASJ exome

AF:

0.157

Gnomad EAS exome

AF:

0.695

Gnomad SAS exome

AF:

0.327

Gnomad FIN exome

AF:

0.200

Gnomad NFE exome

AF:

0.159

Gnomad OTH exome

AF:

0.220

GnomAD4 exome

AF:

0.184

AC:

244905

AN:

1327986

Hom.:

25849

Cov.:

AF XY:

0.188

AC XY:

125428

AN XY:

667038

show subpopulations

Gnomad4 AFR exome

AF:

0.335

Gnomad4 AMR exome

AF:

0.358

Gnomad4 ASJ exome

AF:

0.144

Gnomad4 EAS exome

AF:

0.736

Gnomad4 SAS exome

AF:

0.317

Gnomad4 FIN exome

AF:

0.194

Gnomad4 NFE exome

AF:

0.143

Gnomad4 OTH exome

AF:

0.204

GnomAD4 genome

AF:

0.258

AC:

38743

AN:

149934

Hom.:

6332

Cov.:

AF XY:

0.267

AC XY:

19476

AN XY:

73050

show subpopulations

Gnomad4 AFR

AF:

0.359

Gnomad4 AMR

AF:

0.292

Gnomad4 ASJ

AF:

0.162

Gnomad4 EAS

AF:

0.756

Gnomad4 SAS

AF:

0.352

Gnomad4 FIN

AF:

0.206

Gnomad4 NFE

AF:

0.159

Gnomad4 OTH

AF:

0.244

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2010	The c.3502-14dupT variant is classified as benign because it has been identified in 26.4% of total chromosomes, including 9873 homozygotes, by gnomAD (http://gn omad-beta.broadinstitute.org/) -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2017	Variant summary: The PCDH15 c.3502-14dupT variant involves the duplication of an intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 29147/114904 control chromosomes (3844 homozygotes) at a frequency of 0.2536639, which is approximately 80 times the estimated maximal expected allele frequency of a pathogenic PCDH15 variant (0.0031623), strong evidence that this variant is a benign polymorphism. In addition, one clinical diagnostic laboratory/reputable database has classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Autosomal recessive nonsyndromic hearing loss 23

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Usher syndrome type 1F

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over