rs1900482

Variant names:

• chr10-55348435-C-T
• rs1900482
• NM_001354404.2:c.-155-181784G>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.-155-181784G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 151,814 control chromosomes in the GnomAD database, including 22,774 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 0.54 (22774 hom., cov: 32)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.709
• 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

ENSG00000236744 (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 (AFR) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001354404.2	c.-155-181784G>A		intron_variant	Intron 2 of 34		NP_001341333.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000613346.4	c.-155-181784G>A		intron_variant	Intron 2 of 5	4		ENSP00000481211.1
ENSG00000236744	ENST00000457975.2	n.305+17657G>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82173 AN: 151696 Hom.: 22738 Cov.: 32

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.403

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.521

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

GnomAD4 genome AF: 0.542 AC: 82270 AN: 151814 Hom.: 22774 Cov.: 32 AF XY: 0.538 AC XY: 39899 AN XY: 74206

African (AFR) AF: 0.634 AC: 26247 AN: 41372

American (AMR) AF: 0.545 AC: 8298 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1550 AN: 3470

East Asian (EAS) AF: 0.320 AC: 1649 AN: 5152

South Asian (SAS) AF: 0.442 AC: 2131 AN: 4822

European-Finnish (FIN) AF: 0.515 AC: 5424 AN: 10534

Middle Eastern (MID) AF: 0.399 AC: 115 AN: 288

European-Non Finnish (NFE) AF: 0.518 AC: 35181 AN: 67932

Other (OTH) AF: 0.523 AC: 1102 AN: 2106

Alfa AF: 0.523 Hom.: 56732

Bravo AF: 0.549

Asia WGS AF: 0.422 AC: 1469 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.47
DANN	Benign	0.77
PhyloP100		-0.71
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: rs1900482; hg19: chr10-57108195;