rs10825499

Variant names:

• chr10-55349557-A-T
• rs10825499
• NM_001354404.2:c.-155-182906T>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.-155-182906T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 151,798 control chromosomes in the GnomAD database, including 24,436 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 0.56 (24436 hom., cov: 30)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.294
• 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.683 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.-155-182906T>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.-155-182906T>A		intron	N/A	ENSP00000481211.1
	ENSG00000236744	ENST00000457975.2	TSL:3	n.305+16535T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84726 AN: 151676 Hom.: 24396 Cov.: 30

Gnomad AFR AF: 0.689

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.535

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

GnomAD4 genome AF: 0.559 AC: 84829 AN: 151798 Hom.: 24436 Cov.: 30 AF XY: 0.554 AC XY: 41120 AN XY: 74196

African (AFR) AF: 0.689 AC: 28513 AN: 41368

American (AMR) AF: 0.554 AC: 8442 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1552 AN: 3470

East Asian (EAS) AF: 0.320 AC: 1643 AN: 5132

South Asian (SAS) AF: 0.444 AC: 2136 AN: 4816

European-Finnish (FIN) AF: 0.516 AC: 5448 AN: 10562

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35271 AN: 67896

Other (OTH) AF: 0.538 AC: 1137 AN: 2114

Alfa AF: 0.551 Hom.: 2909

Bravo AF: 0.568

Asia WGS AF: 0.428 AC: 1489 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.81
DANN	Benign	0.61
PhyloP100		-0.29
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: rs10825499; hg19: chr10-57109317;