rs1900425

Variant names:

• chr10-53878980-A-G
• rs1900425
• NM_033056.4:c.3502-12123T>C

Variant summary

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

The NM_033056.4(PCDH15):​c.3502-12123T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 151,534 control chromosomes in the GnomAD database, including 31,321 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 0.64 (31321 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.301
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.3502-12123T>C		intron_variant	Intron 26 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.3502-12123T>C		intron_variant	Intron 26 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.3502-12123T>C		intron_variant	Intron 26 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.3502-12123T>C		intron_variant	Intron 26 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96334 AN: 151416 Hom.: 31316 Cov.: 32

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.812

Gnomad EAS AF: 0.744

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.676

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.680

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

GnomAD4 genome AF: 0.636 AC: 96371 AN: 151534 Hom.: 31321 Cov.: 32 AF XY: 0.643 AC XY: 47614 AN XY: 74016

African (AFR) AF: 0.498 AC: 20563 AN: 41306

American (AMR) AF: 0.743 AC: 11306 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.812 AC: 2800 AN: 3450

East Asian (EAS) AF: 0.744 AC: 3827 AN: 5142

South Asian (SAS) AF: 0.714 AC: 3435 AN: 4812

European-Finnish (FIN) AF: 0.676 AC: 7074 AN: 10470

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45033 AN: 67816

Other (OTH) AF: 0.677 AC: 1427 AN: 2108

Alfa AF: 0.669 Hom.: 19059

Bravo AF: 0.635

Asia WGS AF: 0.675 AC: 2351 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.7
DANN	Benign	0.49
PhyloP100		0.30
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: rs1900425; hg19: chr10-55638740;