10-55214430-T-C

Variant names:

• chr10-55214430-T-C
• rs11004778
• NM_001354404.2:c.-155-47779A>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.-155-47779A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 151,846 control chromosomes in the GnomAD database, including 5,402 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 0.26 (5402 hom., cov: 32)
• Consequence: PCDH15 NM_001354404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 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.-155-47779A>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.-155-47779A>G		intron	N/A	ENSP00000394465.1
	PCDH15	ENST00000613346.4	TSL:4	c.-155-47779A>G		intron	N/A	ENSP00000481211.1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39433 AN: 151728 Hom.: 5402 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.295

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

GnomAD4 genome AF: 0.260 AC: 39434 AN: 151846 Hom.: 5402 Cov.: 32 AF XY: 0.261 AC XY: 19371 AN XY: 74252

African (AFR) AF: 0.163 AC: 6757 AN: 41398

American (AMR) AF: 0.289 AC: 4407 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1088 AN: 3462

East Asian (EAS) AF: 0.280 AC: 1450 AN: 5180

South Asian (SAS) AF: 0.273 AC: 1315 AN: 4818

European-Finnish (FIN) AF: 0.283 AC: 2972 AN: 10516

Middle Eastern (MID) AF: 0.346 AC: 101 AN: 292

European-Non Finnish (NFE) AF: 0.300 AC: 20387 AN: 67916

Other (OTH) AF: 0.290 AC: 611 AN: 2106

Alfa AF: 0.281 Hom.: 15992

Bravo AF: 0.255

Asia WGS AF: 0.238 AC: 825 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.5
DANN	Benign	0.62
PhyloP100		1.3
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: rs11004778; hg19: chr10-56974190;