10-55028375-C-T

Variant names:

• chr10-55028375-C-T
• rs1922155
• NM_001354404.2:c.-79-130875G>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.-79-130875G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 151,420 control chromosomes in the GnomAD database, including 24,880 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 (24880 hom., cov: 31)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354404.2. 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_001354404.2		c.-79-130875G>A		intron	N/A	NP_001341333.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000458638.1	TSL:5	c.-79-130875G>A		intron	N/A	ENSP00000394465.1
	PCDH15	ENST00000613346.4	TSL:4	c.-79-130875G>A		intron	N/A	ENSP00000481211.1

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86169 AN: 151302 Hom.: 24859 Cov.: 31

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.560

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

GnomAD4 genome AF: 0.570 AC: 86239 AN: 151420 Hom.: 24880 Cov.: 31 AF XY: 0.574 AC XY: 42450 AN XY: 73986

African (AFR) AF: 0.514 AC: 21252 AN: 41344

American (AMR) AF: 0.545 AC: 8277 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1632 AN: 3460

East Asian (EAS) AF: 0.750 AC: 3869 AN: 5156

South Asian (SAS) AF: 0.583 AC: 2802 AN: 4808

European-Finnish (FIN) AF: 0.632 AC: 6653 AN: 10530

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

European-Non Finnish (NFE) AF: 0.591 AC: 39933 AN: 67618

Other (OTH) AF: 0.562 AC: 1180 AN: 2100

Alfa AF: 0.445 Hom.: 1282

Bravo AF: 0.558

Asia WGS AF: 0.637 AC: 2211 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.93
DANN	Benign	0.54
PhyloP100		-1.0
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: rs1922155; hg19: chr10-56788135;