10-53857282-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033056.4(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 NM_033056.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.226

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]

ACMG classification

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 GnomAd at 46 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.3718-19C>A		intron_variant		ENST00000644397.2
PCDH15	NM_033056.4	c.3718-19C>A		intron_variant		ENST00000320301.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.3718-19C>A		intron_variant		1	NM_033056.4
PCDH15	ENST00000644397.2	c.3718-19C>A		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3309 AN: 151698 Hom.: 46 Cov.: 31

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

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.: 27 AF XY: 0.0263 AC XY: 18769 AN XY: 713532

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.: 47 Cov.: 31 AF XY: 0.0212 AC XY: 1571 AN XY: 74174

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.: 6

Bravo AF: 0.0222

Asia WGS AF: 0.0210 AC: 71 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

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

Other links and lift over

dbSNP: rs75248212; hg19: chr10-55617042;