chr4-133150817-C-G

Variant names:

• chr4-133150817-C-G
• rs760385127
• NM_032961.3:c.677C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032961.3(PCDH10):​c.677C>G​(p.Pro226Arg) 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCDH10 NM_032961.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21596485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH10	NM_032961.3	c.677C>G	p.Pro226Arg	missense_variant	Exon 1 of 5	ENST00000264360.7	NP_116586.1
PCDH10	NM_020815.3	c.677C>G	p.Pro226Arg	missense_variant	Exon 1 of 1		NP_065866.1
PCDH10	XM_011532150.2	c.677C>G	p.Pro226Arg	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.677C>G	p.Pro226Arg	missense_variant	Exon 1 of 5	1	NM_032961.3	ENSP00000264360.4
PCDH10	ENST00000618019.1	c.677C>G	p.Pro226Arg	missense_variant	Exon 1 of 1	6		ENSP00000480512.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1436228 Hom.: 0 Cov.: 41 AF XY: 0.00000281 AC XY: 2 AN XY: 712048

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.677C>G (p.P226R) alteration is located in exon 1 (coding exon 1) of the PCDH10 gene. This alteration results from a C to G substitution at nucleotide position 677, causing the proline (P) at amino acid position 226 to be replaced by an arginine (R). 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	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.0	.;N
REVEL	Benign	0.091
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.048	D;D
Polyphen		0.77	.;P
Vest4		0.51
MutPred		0.20		Gain of MoRF binding (P = 0.009);Gain of MoRF binding (P = 0.009);
MVP		0.29
ClinPred		0.57	D
GERP RS		3.7
Varity_R		0.54
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

Other links and lift over

dbSNP: rs760385127; hg19: chr4-134071972;