rs2121526

Positions:

• chr10-53927003-A-G
• chr10-53927003-A-T

Variant summary

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

The NM_033056.4(PCDH15):​c.3373+11812T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.962 in 152,264 control chromosomes in the GnomAD database, including 70,490 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 0.96 (70490 hom., cov: 32)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01

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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1	c.3373+11812T>C		intron_variant		ENST00000644397.2	NP_001371069.1
PCDH15	NM_033056.4	c.3373+11812T>C		intron_variant		ENST00000320301.11	NP_149045.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.3373+11812T>C		intron_variant		1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.3373+11812T>C		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.962 AC: 146359 AN: 152146 Hom.: 70430 Cov.: 32

Gnomad AFR AF: 0.989

Gnomad AMI AF: 0.967

Gnomad AMR AF: 0.976

Gnomad ASJ AF: 0.967

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.983

Gnomad FIN AF: 0.939

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.941

Gnomad OTH AF: 0.969

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

GnomAD4 genome AF: 0.962 AC: 146478 AN: 152264 Hom.: 70490 Cov.: 32 AF XY: 0.964 AC XY: 71755 AN XY: 74448

Gnomad4 AFR AF: 0.989

Gnomad4 AMR AF: 0.976

Gnomad4 ASJ AF: 0.967

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.983

Gnomad4 FIN AF: 0.939

Gnomad4 NFE AF: 0.941

Gnomad4 OTH AF: 0.970

Alfa AF: 0.945 Hom.: 6122

Bravo AF: 0.965

Asia WGS AF: 0.991 AC: 3446 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.13
DANN	Benign	0.53

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: rs2121526; hg19: chr10-55686763;