10-55154762-T-C

Variant names:

• chr10-55154762-T-C
• rs2799578
• NM_001354404.2:c.-80+11814A>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+11814A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.941 in 152,184 control chromosomes in the GnomAD database, including 67,663 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 0.94 (67663 hom., cov: 32)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.792
• Publications: 0 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 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.-80+11814A>G		intron	N/A	NP_001341333.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000458638.1	TSL:5	c.-80+11814A>G		intron	N/A	ENSP00000394465.1
	PCDH15	ENST00000613346.4	TSL:4	c.-80+11814A>G		intron	N/A	ENSP00000481211.1

Frequencies

GnomAD3 genomes AF: 0.941 AC: 143132 AN: 152066 Hom.: 67639 Cov.: 32

Gnomad AFR AF: 0.845

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.966

Gnomad ASJ AF: 0.997

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.995

Gnomad FIN AF: 0.990

Gnomad MID AF: 0.953

Gnomad NFE AF: 0.975

Gnomad OTH AF: 0.951

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

GnomAD4 genome AF: 0.941 AC: 143206 AN: 152184 Hom.: 67663 Cov.: 32 AF XY: 0.943 AC XY: 70166 AN XY: 74392

African (AFR) AF: 0.844 AC: 35010 AN: 41488

American (AMR) AF: 0.966 AC: 14750 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.997 AC: 3458 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5165 AN: 5166

South Asian (SAS) AF: 0.995 AC: 4809 AN: 4832

European-Finnish (FIN) AF: 0.990 AC: 10513 AN: 10622

Middle Eastern (MID) AF: 0.956 AC: 281 AN: 294

European-Non Finnish (NFE) AF: 0.975 AC: 66306 AN: 68022

Other (OTH) AF: 0.951 AC: 2005 AN: 2108

Alfa AF: 0.964 Hom.: 186589

Bravo AF: 0.935

Asia WGS AF: 0.987 AC: 3427 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.7
DANN	Benign	0.68
PhyloP100		0.79
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: rs2799578; hg19: chr10-56914522;