10-54860848-G-A

Variant names:

• chr10-54860848-G-A
• rs975809
• NM_001354404.2:c.-29+36602C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354404.2(PCDH15):​c.-29+36602C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 151,926 control chromosomes in the GnomAD database, including 20,789 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 0.52 (20789 hom., cov: 32)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001354404.2	c.-29+36602C>T		intron_variant	Intron 4 of 34		NP_001341333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000458638.1	c.-29+36602C>T		intron_variant	Intron 3 of 5	5		ENSP00000394465.1
PCDH15	ENST00000613346.4	c.-29+36602C>T		intron_variant	Intron 4 of 5	4		ENSP00000481211.1

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78631 AN: 151808 Hom.: 20773 Cov.: 32

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.824

Gnomad SAS AF: 0.583

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.497

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

GnomAD4 genome AF: 0.518 AC: 78699 AN: 151926 Hom.: 20789 Cov.: 32 AF XY: 0.524 AC XY: 38942 AN XY: 74262

African (AFR) AF: 0.464 AC: 19226 AN: 41428

American (AMR) AF: 0.569 AC: 8678 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1658 AN: 3470

East Asian (EAS) AF: 0.824 AC: 4249 AN: 5156

South Asian (SAS) AF: 0.583 AC: 2807 AN: 4812

European-Finnish (FIN) AF: 0.555 AC: 5856 AN: 10560

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.511 AC: 34698 AN: 67944

Other (OTH) AF: 0.500 AC: 1057 AN: 2114

Alfa AF: 0.514 Hom.: 20110

Bravo AF: 0.514

Asia WGS AF: 0.693 AC: 2406 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	6.4
DANN	Benign	0.62
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs975809; hg19: chr10-56620608;