rs4592338

Positions:

• chr10-54338664-C-A
• chr10-54338664-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033056.4(PCDH15):​c.594+7701G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0705 in 152,124 control chromosomes in the GnomAD database, including 489 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 0.071 (489 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00700

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1	c.594+7701G>T		intron_variant		ENST00000644397.2	NP_001371069.1
PCDH15	NM_033056.4	c.594+7701G>T		intron_variant		ENST00000320301.11	NP_149045.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.594+7701G>T		intron_variant		1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.594+7701G>T		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.0705 AC: 10710 AN: 152006 Hom.: 485 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.0465

Gnomad SAS AF: 0.0711

Gnomad FIN AF: 0.0755

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0364

Gnomad OTH AF: 0.0608

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

GnomAD4 genome AF: 0.0705 AC: 10728 AN: 152124 Hom.: 489 Cov.: 32 AF XY: 0.0722 AC XY: 5373 AN XY: 74370

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.0465

Gnomad4 SAS AF: 0.0701

Gnomad4 FIN AF: 0.0755

Gnomad4 NFE AF: 0.0364

Gnomad4 OTH AF: 0.0649

Alfa AF: 0.0407 Hom.: 338

Bravo AF: 0.0756

Asia WGS AF: 0.0910 AC: 316 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.7
DANN	Benign	0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4592338; hg19: chr10-56098424;