chr10-55317875-C-T

Variant names:

• chr10-55317875-C-T
• rs2441760
• NM_001354404.2:c.-155-151224G>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.-155-151224G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.741 in 152,046 control chromosomes in the GnomAD database, including 42,580 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 0.74 (42580 hom., cov: 32)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.610
• Publications: 2 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

ENSG00000236744 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001354404.2	c.-155-151224G>A		intron_variant	Intron 2 of 34		NP_001341333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000458638.1	c.-156+1724G>A		intron_variant	Intron 1 of 5	5		ENSP00000394465.1
PCDH15	ENST00000613346.4	c.-155-151224G>A		intron_variant	Intron 2 of 5	4		ENSP00000481211.1
ENSG00000236744	ENST00000457975.2	n.305+48217G>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.741 AC: 112630 AN: 151926 Hom.: 42533 Cov.: 32

Gnomad AFR AF: 0.832

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.738

Gnomad OTH AF: 0.725

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

GnomAD4 genome AF: 0.741 AC: 112742 AN: 152046 Hom.: 42580 Cov.: 32 AF XY: 0.736 AC XY: 54744 AN XY: 74336

African (AFR) AF: 0.832 AC: 34499 AN: 41468

American (AMR) AF: 0.706 AC: 10781 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2446 AN: 3470

East Asian (EAS) AF: 0.321 AC: 1657 AN: 5156

South Asian (SAS) AF: 0.628 AC: 3030 AN: 4824

European-Finnish (FIN) AF: 0.721 AC: 7621 AN: 10568

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.738 AC: 50164 AN: 67972

Other (OTH) AF: 0.725 AC: 1531 AN: 2112

Alfa AF: 0.735 Hom.: 69588

Bravo AF: 0.746

Asia WGS AF: 0.507 AC: 1763 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.31
DANN	Benign	0.64
PhyloP100		-0.61
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: rs2441760; hg19: chr10-57077635;