chr10-55343600-A-G

Variant names:

• chr10-55343600-A-G
• rs2218582
• NM_001354404.2:c.-155-176949T>C

Variant summary

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

The NM_001354404.2(PCDH15):​c.-155-176949T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 151,472 control chromosomes in the GnomAD database, including 23,534 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 0.55 (23534 hom., cov: 30)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• 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 Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Usher syndrome type 1

  Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.652 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_001354404.2		c.-155-176949T>C		intron	N/A	NP_001341333.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000613346.4	TSL:4	c.-155-176949T>C		intron	N/A	ENSP00000481211.1	A0A087WXQ6
	ENSG00000236744	ENST00000457975.2	TSL:3	n.305+22492T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83381 AN: 151352 Hom.: 23498 Cov.: 30

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.530

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

GnomAD4 genome AF: 0.551 AC: 83481 AN: 151472 Hom.: 23534 Cov.: 30 AF XY: 0.546 AC XY: 40408 AN XY: 73962

African (AFR) AF: 0.659 AC: 27215 AN: 41316

American (AMR) AF: 0.549 AC: 8343 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1697 AN: 3466

East Asian (EAS) AF: 0.323 AC: 1648 AN: 5104

South Asian (SAS) AF: 0.444 AC: 2135 AN: 4812

European-Finnish (FIN) AF: 0.515 AC: 5354 AN: 10394

Middle Eastern (MID) AF: 0.397 AC: 115 AN: 290

European-Non Finnish (NFE) AF: 0.520 AC: 35277 AN: 67882

Other (OTH) AF: 0.532 AC: 1124 AN: 2112

Alfa AF: 0.550 Hom.: 3103

Bravo AF: 0.559

Asia WGS AF: 0.425 AC: 1478 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.22
DANN	Benign	0.78
PhyloP100		-1.5
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: rs2218582; hg19: chr10-57103360;