Genetic Variant PCDH10:p.Met12Val (chr4-133150174-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032961.3(PCDH10):c.34A>G(p.Met12Val) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M12L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PCDH10
NM_032961.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.56

Publications

1 publications found

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:

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

PCDH10-DT links:

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ACMG classification

Classification was made for transcript

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=0.07889196).

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>G	p.Met12Val	missense	Exon 1 of 5	NP_116586.1	Q9P2E7-1
	PCDH10	NM_020815.3		c.34A>G	p.Met12Val	missense	Exon 1 of 1	NP_065866.1	Q9P2E7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCDH10	ENST00000264360.7	TSL:1 MANE Select	c.34A>G	p.Met12Val	missense	Exon 1 of 5	ENSP00000264360.4	Q9P2E7-1
PCDH10	ENST00000618019.1	TSL:6	c.34A>G	p.Met12Val	missense	Exon 1 of 1	ENSP00000480512.1	Q9P2E7-2
PCDH10-DT	ENST00000732819.1		n.219+677T>C		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000435

AC:

AN:

230034

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000322

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1438396

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713802

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32604

American (AMR)

AF:

0.0000245

AC:

AN:

40792

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24114

East Asian (EAS)

AF:

0.00

AC:

AN:

39574

South Asian (SAS)

AF:

0.00

AC:

AN:

81666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5578

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102088

Other (OTH)

AF:

0.00

AC:

AN:

59366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.077

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.73

M_CAP

Benign

0.0038

MetaRNN

Benign

0.079

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.45

PhyloP100

3.6

PrimateAI

Benign

0.47

PROVEAN

Benign

0.18

REVEL

Benign

0.079

Sift

Benign

0.87

Sift4G

Benign

0.61

Polyphen

0.0010

Vest4

0.23

MutPred

0.41

Gain of catalytic residue at M12 (P = 0.1354)

MVP

0.20

ClinPred

0.21

GERP RS

4.9

Varity_R

0.10

gMVP

0.24

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over