10-55335493-C-T

Variant names:

• chr10-55335493-C-T
• rs1900472
• NM_001354404.2:c.-155-168842G>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.-155-168842G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.533 in 152,074 control chromosomes in the GnomAD database, including 21,975 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 0.53 (21975 hom., cov: 32)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.369
• 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

ENSG00000236744 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.588 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_001354404.2		c.-155-168842G>A		intron	N/A	NP_001341333.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000613346.4	TSL:4	c.-155-168842G>A		intron	N/A	ENSP00000481211.1
	ENSG00000236744	ENST00000457975.2	TSL:3	n.305+30599G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.533 AC: 80990 AN: 151956 Hom.: 21944 Cov.: 32

Gnomad AFR AF: 0.594

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.518

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

GnomAD4 genome AF: 0.533 AC: 81081 AN: 152074 Hom.: 21975 Cov.: 32 AF XY: 0.528 AC XY: 39279 AN XY: 74346

African (AFR) AF: 0.594 AC: 24633 AN: 41472

American (AMR) AF: 0.546 AC: 8337 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1551 AN: 3470

East Asian (EAS) AF: 0.320 AC: 1655 AN: 5170

South Asian (SAS) AF: 0.443 AC: 2137 AN: 4824

European-Finnish (FIN) AF: 0.516 AC: 5457 AN: 10574

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35518 AN: 67970

Other (OTH) AF: 0.521 AC: 1101 AN: 2114

Alfa AF: 0.533 Hom.: 4528

Bravo AF: 0.539

Asia WGS AF: 0.423 AC: 1472 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.3
DANN	Benign	0.77
PhyloP100		-0.37
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: rs1900472; hg19: chr10-57095253;