Genetic Variant PCDH10:p.Pro226Leu (chr4-133150817-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032961.3(PCDH10):c.677C>T(p.Pro226Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,436,228 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P226R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PCDH10
NM_032961.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.87

Variant links:

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]

PCDH10 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1532107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH10	NM_032961.3 link	c.677C>T	p.Pro226Leu	missense_variant	Exon 1 of 5	ENST00000264360.7	NP_116586.1	Q9P2E7-1X5D999Q9NSR3
PCDH10	NM_020815.3 link	c.677C>T	p.Pro226Leu	missense_variant	Exon 1 of 1		NP_065866.1	Q9P2E7-2
PCDH10	XM_011532150.2 link	c.677C>T	p.Pro226Leu	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 link	c.677C>T	p.Pro226Leu	missense_variant	Exon 1 of 5	1	NM_032961.3	ENSP00000264360.4		Q9P2E7-1
PCDH10	ENST00000618019.1 link	c.677C>T	p.Pro226Leu	missense_variant	Exon 1 of 1	6		ENSP00000480512.1		Q9P2E7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000873

AC:

AN:

229210

Hom.:

AF XY:

0.00000810

AC XY:

AN XY:

123520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000549

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000946

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1436228

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712048

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.08e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.677C>T (p.P226L) 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 677, causing the proline (P) at amino acid position 226 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

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

.;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.017

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.11

N;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.1

.;N

REVEL

Benign

0.033

Sift

Pathogenic

0.0

.;D

Sift4G

Benign

0.063

T;T

Polyphen

0.0010

.;B

Vest4

0.38

MutPred

0.23

Gain of stability (P = 0.0053);Gain of stability (P = 0.0053);

MVP

0.29

ClinPred

0.36

GERP RS

3.7

Varity_R

0.42

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over