10-55049046-T-C

Variant names:

• chr10-55049046-T-C
• rs10763176
• NM_001354404.2:c.-80+117530A>G

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+117530A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 151,700 control chromosomes in the GnomAD database, including 23,134 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 0.54 (23134 hom., cov: 32)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.554
• 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 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 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.-80+117530A>G		intron	N/A	NP_001341333.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000458638.1	TSL:5	c.-80+117530A>G		intron	N/A	ENSP00000394465.1	A2A3D9
	PCDH15	ENST00000613346.4	TSL:4	c.-80+117530A>G		intron	N/A	ENSP00000481211.1	A0A087WXQ6

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82398 AN: 151582 Hom.: 23122 Cov.: 32

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.536

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

GnomAD4 genome AF: 0.543 AC: 82449 AN: 151700 Hom.: 23134 Cov.: 32 AF XY: 0.548 AC XY: 40622 AN XY: 74120

African (AFR) AF: 0.422 AC: 17472 AN: 41418

American (AMR) AF: 0.538 AC: 8211 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1656 AN: 3462

East Asian (EAS) AF: 0.750 AC: 3870 AN: 5158

South Asian (SAS) AF: 0.582 AC: 2806 AN: 4820

European-Finnish (FIN) AF: 0.629 AC: 6618 AN: 10526

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.591 AC: 40046 AN: 67758

Other (OTH) AF: 0.538 AC: 1131 AN: 2102

Alfa AF: 0.570 Hom.: 18037

Bravo AF: 0.529

Asia WGS AF: 0.628 AC: 2180 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.1
DANN	Benign	0.57
PhyloP100		-0.55
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: rs10763176; hg19: chr10-56808806;