chr10-54006668-C-T

Variant names:

• chr10-54006668-C-T
• rs5003374
• NM_033056.4:c.2752-10903G>A

Variant summary

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

The NM_033056.4(PCDH15):​c.2752-10903G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 151,964 control chromosomes in the GnomAD database, including 25,421 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 0.56 (25421 hom., cov: 31)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.795
• Publications: 7 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033056.4. 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_033056.4	MANE Plus Clinical	c.2752-10903G>A		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.2752-10903G>A		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.2767-10903G>A		intron	N/A	NP_001136235.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.2752-10903G>A		intron	N/A	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.2752-10903G>A		intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.2773-10903G>A		intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85667 AN: 151846 Hom.: 25427 Cov.: 31

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.603

Gnomad ASJ AF: 0.715

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.655

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.609

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

GnomAD4 genome AF: 0.564 AC: 85701 AN: 151964 Hom.: 25421 Cov.: 31 AF XY: 0.570 AC XY: 42300 AN XY: 74272

African (AFR) AF: 0.370 AC: 15345 AN: 41428

American (AMR) AF: 0.603 AC: 9195 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.715 AC: 2484 AN: 3472

East Asian (EAS) AF: 0.475 AC: 2444 AN: 5148

South Asian (SAS) AF: 0.703 AC: 3383 AN: 4812

European-Finnish (FIN) AF: 0.655 AC: 6927 AN: 10580

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43722 AN: 67960

Other (OTH) AF: 0.605 AC: 1276 AN: 2108

Alfa AF: 0.614 Hom.: 58259

Bravo AF: 0.547

Asia WGS AF: 0.562 AC: 1958 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.49
DANN	Benign	0.60
PhyloP100		-0.80
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5003374; hg19: chr10-55766428;