chr10-53857282-G-T

Position:

chr10-53857282-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000320301.11(PCDH15):c.3718-19C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,582,082 control chromosomes in the GnomAD database, including 600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 47 hom., cov: 31)

Exomes 𝑓: 0.026 ( 553 hom. )

Consequence

PCDH15
ENST00000320301.11 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.226

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 10-53857282-G-T is Benign according to our data. Variant chr10-53857282-G-T is described in ClinVar as [Benign]. Clinvar id is 46472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53857282-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0219 (3318/151816) while in subpopulation SAS AF= 0.0383 (184/4798). AF 95% confidence interval is 0.0338. There are 47 homozygotes in gnomad4. There are 1571 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 47 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1 linkuse as main transcript	c.3718-19C>A		intron_variant		ENST00000644397.2	NP_001371069.1
PCDH15	NM_033056.4 linkuse as main transcript	c.3718-19C>A		intron_variant		ENST00000320301.11	NP_149045.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 linkuse as main transcript	c.3718-19C>A		intron_variant		1	NM_033056.4	ENSP00000322604		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.3718-19C>A		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3309

AN:

151698

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0152

Gnomad AMI

AF:

0.0319

Gnomad AMR

AF:

0.0284

Gnomad ASJ

AF:

0.0298

Gnomad EAS

AF:

0.00794

Gnomad SAS

AF:

0.0373

Gnomad FIN

AF:

0.00654

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0259

Gnomad OTH

AF:

0.0294

GnomAD3 exomes

AF:

0.0231

AC:

5769

AN:

250162

Hom.:

101

AF XY:

0.0248

AC XY:

3363

AN XY:

135420

show subpopulations

Gnomad AFR exome

AF:

0.0147

Gnomad AMR exome

AF:

0.0194

Gnomad ASJ exome

AF:

0.0336

Gnomad EAS exome

AF:

0.0113

Gnomad SAS exome

AF:

0.0402

Gnomad FIN exome

AF:

0.00587

Gnomad NFE exome

AF:

0.0245

Gnomad OTH exome

AF:

0.0315

GnomAD4 exome

AF:

0.0255

AC:

36543

AN:

1430266

Hom.:

553

Cov.:

AF XY:

0.0263

AC XY:

18769

AN XY:

713532

show subpopulations

Gnomad4 AFR exome

AF:

0.0140

Gnomad4 AMR exome

AF:

0.0201

Gnomad4 ASJ exome

AF:

0.0331

Gnomad4 EAS exome

AF:

0.00620

Gnomad4 SAS exome

AF:

0.0407

Gnomad4 FIN exome

AF:

0.00619

Gnomad4 NFE exome

AF:

0.0262

Gnomad4 OTH exome

AF:

0.0268

GnomAD4 genome

AF:

0.0219

AC:

3318

AN:

151816

Hom.:

Cov.:

AF XY:

0.0212

AC XY:

1571

AN XY:

74174

show subpopulations

Gnomad4 AFR

AF:

0.0153

Gnomad4 AMR

AF:

0.0283

Gnomad4 ASJ

AF:

0.0298

Gnomad4 EAS

AF:

0.00796

Gnomad4 SAS

AF:

0.0383

Gnomad4 FIN

AF:

0.00654

Gnomad4 NFE

AF:

0.0259

Gnomad4 OTH

AF:

0.0290

Alfa

AF:

0.0156

Hom.:

Bravo

AF:

0.0222

Asia WGS

AF:

0.0210

AC:

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2016	Variant summary: The PCDH15 c.3718-19C>A variant involves the alteration of a non-conserved intronic nucleotide. Mutation Taster predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 2786/119520 control chromosomes (53 homozygotes) at a frequency of 0.0233099, which is approximately 7 times the estimated maximal expected allele frequency of a pathogenic PCDH15 variant (0.0031623), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories and a reputable database have classified this variant as benign. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2012	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	Jun 01, 2013	proposed classification - variant undergoing re-assessment, contact laboratory -

Usher syndrome type 1F

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.18

DANN

Benign

0.43

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