4-133150628-C-T

Variant names:

• chr4-133150628-C-T
• rs935822454
• NM_032961.3:c.488C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032961.3(PCDH10):​c.488C>T​(p.Pro163Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: PCDH10 NM_032961.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

Genes affected

PCDH10 (HGNC:13404): (protocadherin 10) This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. This family member contains 6 extracellular cadherin domains, a transmembrane domain and a cytoplasmic tail differing from those of the classical cadherins. The encoded protein is a cadherin-related neuronal receptor thought to function in the establishment of specific cell-cell connections in the brain. This gene plays a role in inhibiting cancer cell motility and cell migration. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31034368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH10	NM_032961.3	c.488C>T	p.Pro163Leu	missense_variant	Exon 1 of 5	ENST00000264360.7	NP_116586.1
PCDH10	NM_020815.3	c.488C>T	p.Pro163Leu	missense_variant	Exon 1 of 1		NP_065866.1
PCDH10	XM_011532150.2	c.488C>T	p.Pro163Leu	missense_variant	Exon 1 of 5		XP_011530452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH10	ENST00000264360.7	c.488C>T	p.Pro163Leu	missense_variant	Exon 1 of 5	1	NM_032961.3	ENSP00000264360.4
PCDH10	ENST00000618019.1	c.488C>T	p.Pro163Leu	missense_variant	Exon 1 of 1	6		ENSP00000480512.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151942 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151942 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74172

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.488C>T (p.P163L) alteration is located in exon 1 (coding exon 1) of the PCDH10 gene. This alteration results from a C to T substitution at nucleotide position 488, causing the proline (P) at amino acid position 163 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	.;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T;D
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.3	.;D
REVEL	Benign	0.083
Sift	Benign	0.069	.;T
Sift4G	Benign	0.15	T;T
Polyphen		0.18	.;B
Vest4		0.40
MutPred		0.49		Loss of catalytic residue at P163 (P = 0.0146);Loss of catalytic residue at P163 (P = 0.0146);
MVP		0.38
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.52
gMVP		0.42

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: rs935822454; hg19: chr4-134071783;