NM_001354404.2:c.-80+131258G>T

Variant names:

• chr10-55035318-C-A
• rs1922166
• NM_001354404.2:c.-80+131258G>T

Variant summary

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

The NM_001354404.2(PCDH15):​c.-80+131258G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 151,824 control chromosomes in the GnomAD database, including 25,066 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 (25066 hom., cov: 32)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.967
• 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=-0.96).
• 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_001354404.2	c.-80+131258G>T		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.-80+131258G>T		intron_variant	Intron 2 of 5	5		ENSP00000394465.1
PCDH15	ENST00000613346.4	c.-80+131258G>T		intron_variant	Intron 3 of 5	4		ENSP00000481211.1

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86603 AN: 151706 Hom.: 25045 Cov.: 32

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.487

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: 0.571 AC: 86672 AN: 151824 Hom.: 25066 Cov.: 32 AF XY: 0.575 AC XY: 42651 AN XY: 74182

African (AFR) AF: 0.515 AC: 21327 AN: 41404

American (AMR) AF: 0.552 AC: 8424 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 1652 AN: 3468

East Asian (EAS) AF: 0.751 AC: 3861 AN: 5144

South Asian (SAS) AF: 0.582 AC: 2802 AN: 4818

European-Finnish (FIN) AF: 0.631 AC: 6646 AN: 10540

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.591 AC: 40141 AN: 67882

Other (OTH) AF: 0.559 AC: 1181 AN: 2112

Alfa AF: 0.576 Hom.: 69283

Bravo AF: 0.560

Asia WGS AF: 0.637 AC: 2212 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.24
DANN	Benign	0.29
PhyloP100		-0.97
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: rs1922166; hg19: chr10-56795078;