Genetic Variant PCDH12:p.Asp1149His (chr5-141945491-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_016580.4(PCDH12):c.3445G>C(p.Asp1149His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. D1149Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

PCDH12
NM_016580.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.13

Publications

0 publications found

Variant links:

Genes affected

PCDH12 (HGNC:8657): (protocadherin 12) This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The encoded protein consists of an extracellular domain containing 6 cadherin repeats, a transmembrane domain and a cytoplasmic tail that differs from those of the classical cadherins. The gene localizes to the region on chromosome 5 where the protocadherin gene clusters reside. The exon organization of this transcript is similar to that of the gene cluster transcripts, notably the first large exon, but no significant sequence homology exists. The function of this cellular adhesion protein is undetermined but mouse protocadherin 12 does not bind catenins and appears to have no affect on cell migration or growth. [provided by RefSeq, Jul 2008]

PCDH12 links:

DELE1 (HGNC:28969): (DAP3 binding cell death enhancer 1) Enables protein kinase binding activity and protein serine/threonine kinase activator activity. Involved in HRI-mediated signaling; extrinsic apoptotic signaling pathway via death domain receptors; and regulation of cysteine-type endopeptidase activity involved in apoptotic process. Located in cytosol and mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

DELE1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38638437).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016580.4. 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
	PCDH12	NM_016580.4	MANE Select	c.3445G>C	p.Asp1149His	missense	Exon 4 of 4	NP_057664.1	Q9NPG4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH12	ENST00000231484.4	TSL:1 MANE Select	c.3445G>C	p.Asp1149His	missense	Exon 4 of 4	ENSP00000231484.3	Q9NPG4
	DELE1	ENST00000895929.1		c.*2-1309C>G		intron	N/A	ENSP00000565988.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

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

0.31

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

M_CAP

Benign

0.036

MetaRNN

Benign

0.39

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.5

PhyloP100

4.1

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.9

REVEL

Benign

0.25

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.41

MutPred

0.24

Loss of sheet (P = 0.0457)

MVP

0.93

MPC

0.73

ClinPred

0.96

GERP RS

6.1

Varity_R

0.55

gMVP

0.53

Mutation Taster

=54/46

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