NM_033056.4:c.2752-12097G>A

Variant names:

• chr10-54007862-C-T
• rs10509003
• NM_033056.4:c.2752-12097G>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.2752-12097G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 151,896 control chromosomes in the GnomAD database, including 10,140 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 0.33 (10140 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.503
• Publications: 3 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=-0.59).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.2752-12097G>A		intron_variant	Intron 20 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.2752-12097G>A		intron_variant	Intron 20 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.2752-12097G>A		intron_variant	Intron 20 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.2752-12097G>A		intron_variant	Intron 20 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50387 AN: 151778 Hom.: 10142 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.394

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

GnomAD4 genome AF: 0.332 AC: 50395 AN: 151896 Hom.: 10140 Cov.: 32 AF XY: 0.332 AC XY: 24630 AN XY: 74198

African (AFR) AF: 0.127 AC: 5254 AN: 41458

American (AMR) AF: 0.394 AC: 5997 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 1844 AN: 3470

East Asian (EAS) AF: 0.0160 AC: 83 AN: 5178

South Asian (SAS) AF: 0.286 AC: 1381 AN: 4822

European-Finnish (FIN) AF: 0.423 AC: 4446 AN: 10518

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.441 AC: 29958 AN: 67900

Other (OTH) AF: 0.390 AC: 823 AN: 2110

Alfa AF: 0.383 Hom.: 3274

Bravo AF: 0.323

Asia WGS AF: 0.158 AC: 554 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.9
DANN	Benign	0.64
PhyloP100		0.50
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: rs10509003; hg19: chr10-55767622;