10-55017264-T-C

Variant names:

• chr10-55017264-T-C
• rs10763170
• NM_001354404.2:c.-79-119764A>G

Variant summary

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

The NM_001354404.2(PCDH15):​c.-79-119764A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 151,866 control chromosomes in the GnomAD database, including 22,054 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 0.53 (22054 hom., cov: 32)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• 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=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354404.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_001354404.2		c.-79-119764A>G		intron	N/A	NP_001341333.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000458638.1	TSL:5	c.-79-119764A>G		intron	N/A	ENSP00000394465.1
	PCDH15	ENST00000613346.4	TSL:4	c.-79-119764A>G		intron	N/A	ENSP00000481211.1

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79842 AN: 151752 Hom.: 22052 Cov.: 32

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.753

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.522

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

GnomAD4 genome AF: 0.526 AC: 79868 AN: 151866 Hom.: 22054 Cov.: 32 AF XY: 0.531 AC XY: 39431 AN XY: 74210

African (AFR) AF: 0.362 AC: 14996 AN: 41444

American (AMR) AF: 0.528 AC: 8037 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1640 AN: 3468

East Asian (EAS) AF: 0.753 AC: 3874 AN: 5144

South Asian (SAS) AF: 0.590 AC: 2834 AN: 4806

European-Finnish (FIN) AF: 0.630 AC: 6654 AN: 10566

Middle Eastern (MID) AF: 0.473 AC: 138 AN: 292

European-Non Finnish (NFE) AF: 0.590 AC: 40085 AN: 67906

Other (OTH) AF: 0.525 AC: 1110 AN: 2114

Alfa AF: 0.556 Hom.: 66104

Bravo AF: 0.509

Asia WGS AF: 0.630 AC: 2189 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.097
DANN	Benign	0.48
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: rs10763170; hg19: chr10-56777024;