chr10-54448976-G-A

Variant names:

• chr10-54448976-G-A
• rs2026414
• NM_033056.4:c.158-70034C>T

Variant summary

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

The NM_033056.4(PCDH15):​c.158-70034C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 151,470 control chromosomes in the GnomAD database, including 21,083 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 0.50 (21083 hom., cov: 31)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.03
• Publications: 5 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 (NFE) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.158-70034C>T		intron_variant	Intron 3 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.158-70034C>T		intron_variant	Intron 3 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.158-70034C>T		intron_variant	Intron 3 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.158-70034C>T		intron_variant	Intron 3 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75619 AN: 151352 Hom.: 21079 Cov.: 31

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.542

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

GnomAD4 genome AF: 0.499 AC: 75654 AN: 151470 Hom.: 21083 Cov.: 31 AF XY: 0.495 AC XY: 36645 AN XY: 73984

African (AFR) AF: 0.255 AC: 10535 AN: 41366

American (AMR) AF: 0.603 AC: 9131 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 2066 AN: 3458

East Asian (EAS) AF: 0.334 AC: 1716 AN: 5134

South Asian (SAS) AF: 0.401 AC: 1933 AN: 4816

European-Finnish (FIN) AF: 0.552 AC: 5820 AN: 10550

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.627 AC: 42414 AN: 67688

Other (OTH) AF: 0.540 AC: 1135 AN: 2100

Alfa AF: 0.566 Hom.: 50593

Bravo AF: 0.493

Asia WGS AF: 0.412 AC: 1435 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	0.0090
DANN	Benign	0.38
PhyloP100		-2.0
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: rs2026414; hg19: chr10-56208736;