4-133150174-A-T

Variant names:

• chr4-133150174-A-T
• rs1276183716
• NM_032961.3:c.34A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032961.3(PCDH10):​c.34A>T​(p.Met12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PCDH10 NM_032961.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.56
• Publications: 1 publications found

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-DT (HGNC:53036): (PCDH10 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.090471566).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032961.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH10	NM_032961.3	MANE Select	c.34A>T	p.Met12Leu	missense	Exon 1 of 5	NP_116586.1	Q9P2E7-1
	PCDH10	NM_020815.3		c.34A>T	p.Met12Leu	missense	Exon 1 of 1	NP_065866.1	Q9P2E7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH10	ENST00000264360.7	TSL:1 MANE Select	c.34A>T	p.Met12Leu	missense	Exon 1 of 5	ENSP00000264360.4	Q9P2E7-1
	PCDH10	ENST00000618019.1	TSL:6	c.34A>T	p.Met12Leu	missense	Exon 1 of 1	ENSP00000480512.1	Q9P2E7-2
	PCDH10-DT	ENST00000732819.1		n.219+677T>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438396 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 713802

African (AFR) AF: 0.00 AC: 0 AN: 32604

American (AMR) AF: 0.00 AC: 0 AN: 40792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24114

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 81666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102088

Other (OTH) AF: 0.00 AC: 0 AN: 59366

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.95	N
PhyloP100		3.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.11
Sift	Benign	0.75	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.44		Loss of sheet (P = 0.0315)
MVP		0.26
ClinPred		0.81	D
GERP RS		4.9
Varity_R		0.13
gMVP		0.19
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs1276183716; hg19: chr4-134071329;