10-55024936-G-T

Variant names:

• chr10-55024936-G-T
• rs11004683
• NM_001354404.2:c.-79-127436C>A

Variant summary

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

The NM_001354404.2(PCDH15):​c.-79-127436C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 151,720 control chromosomes in the GnomAD database, including 24,901 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 0.57 (24901 hom., cov: 31)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.330
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001354404.2	c.-79-127436C>A		intron_variant	Intron 3 of 34		NP_001341333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000458638.1	c.-79-127436C>A		intron_variant	Intron 2 of 5	5		ENSP00000394465.1
PCDH15	ENST00000613346.4	c.-79-127436C>A		intron_variant	Intron 3 of 5	4		ENSP00000481211.1

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86300 AN: 151606 Hom.: 24881 Cov.: 31

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.557

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

GnomAD4 genome AF: 0.569 AC: 86368 AN: 151720 Hom.: 24901 Cov.: 31 AF XY: 0.573 AC XY: 42503 AN XY: 74130

African (AFR) AF: 0.514 AC: 21241 AN: 41336

American (AMR) AF: 0.544 AC: 8288 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1637 AN: 3472

East Asian (EAS) AF: 0.754 AC: 3883 AN: 5148

South Asian (SAS) AF: 0.583 AC: 2804 AN: 4812

European-Finnish (FIN) AF: 0.627 AC: 6594 AN: 10516

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.591 AC: 40101 AN: 67894

Other (OTH) AF: 0.559 AC: 1178 AN: 2108

Alfa AF: 0.571 Hom.: 3052

Bravo AF: 0.558

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.38
DANN	Benign	0.65
PhyloP100		-0.33
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: rs11004683; hg19: chr10-56784696;