rs11004359

Variant names:

• chr10-54541790-G-A
• rs11004359
• NM_033056.4:c.92-13913C>T

Variant summary

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

The NM_033056.4(PCDH15):​c.92-13913C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,092 control chromosomes in the GnomAD database, including 1,621 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 0.13 (1621 hom., cov: 33)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.253
• Publications: 1 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

ENSG00000234173 (HGNC:):

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 (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.92-13913C>T		intron_variant	Intron 2 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.92-13913C>T		intron_variant	Intron 2 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.92-13913C>T		intron_variant	Intron 2 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.92-13913C>T		intron_variant	Intron 2 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19060 AN: 151974 Hom.: 1618 Cov.: 33

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.0718

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.147

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

GnomAD4 genome AF: 0.125 AC: 19065 AN: 152092 Hom.: 1621 Cov.: 33 AF XY: 0.127 AC XY: 9458 AN XY: 74342

African (AFR) AF: 0.0439 AC: 1825 AN: 41530

American (AMR) AF: 0.164 AC: 2500 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 530 AN: 3466

East Asian (EAS) AF: 0.359 AC: 1850 AN: 5156

South Asian (SAS) AF: 0.244 AC: 1178 AN: 4826

European-Finnish (FIN) AF: 0.0718 AC: 759 AN: 10574

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9959 AN: 67950

Other (OTH) AF: 0.150 AC: 317 AN: 2114

Alfa AF: 0.149 Hom.: 1124

Bravo AF: 0.130

Asia WGS AF: 0.266 AC: 921 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	9.5
DANN	Benign	0.33
PhyloP100		0.25
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: rs11004359; hg19: chr10-56301550;