4-133150201-C-T

Position:

• chr4-133150201-C-T

Variant summary

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

The NM_032961.3(PCDH10):​c.61C>T​(p.His21Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PCDH10 NM_032961.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH10	NM_032961.3	c.61C>T	p.His21Tyr	missense_variant	1/5	ENST00000264360.7
PCDH10	NM_020815.3	c.61C>T	p.His21Tyr	missense_variant	1/1
PCDH10	XM_011532150.2	c.61C>T	p.His21Tyr	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH10	ENST00000264360.7	c.61C>T	p.His21Tyr	missense_variant	1/5	1	NM_032961.3	P1
PCDH10	ENST00000618019.1	c.61C>T	p.His21Tyr	missense_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2023

The c.61C>T (p.H21Y) 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 61, causing the histidine (H) at amino acid position 21 to be replaced by a tyrosine (Y). 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	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0062	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	.;N
REVEL	Benign	0.087
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.84	.;P
Vest4		0.29
MutPred		0.49		Loss of disorder (P = 0.0508);Loss of disorder (P = 0.0508);
MVP		0.28
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.66
gMVP		0.41

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: rs1726626257; hg19: chr4-134071356;