Genetic Variant PCBD2:p.Ala126Val (chr5-134960665-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032151.5(PCBD2):c.377C>T(p.Ala126Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A126P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PCBD2
NM_032151.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66

Variant links:

Genes affected

PCBD2 (HGNC:24474): (pterin-4 alpha-carbinolamine dehydratase 2) Predicted to enable 4-alpha-hydroxytetrahydrobiopterin dehydratase activity. Involved in positive regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

PCBD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.085722566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCBD2	NM_032151.5 link	c.377C>T	p.Ala126Val	missense_variant	Exon 4 of 4	ENST00000254908.11	NP_115527.3	Q9H0N5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCBD2	ENST00000254908.11 link	c.377C>T	p.Ala126Val	missense_variant	Exon 4 of 4	1	NM_032151.5	ENSP00000254908.6	Q9H0N5
PCBD2	ENST00000512783.5 link	c.377C>T	p.Ala126Val	missense_variant	Exon 4 of 5	1		ENSP00000421544.1	Q9H0N5
PCBD2	ENST00000504352.1 link	n.344C>T		non_coding_transcript_exon_variant	Exon 4 of 8	5		ENSP00000426161.1	H0YA52

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

249076

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000274

AC:

AN:

1458752

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725896

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.377C>T (p.A126V) alteration is located in exon 4 (coding exon 4) of the PCBD2 gene. This alteration results from a C to T substitution at nucleotide position 377, causing the alanine (A) at amino acid position 126 to be replaced by a valine (V). 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

-0.15

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.53

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.82

.;T

M_CAP

Benign

0.057

MetaRNN

Benign

0.086

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.69

N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.54

N;N

REVEL

Benign

0.21

Sift

Benign

0.59

T;T

Sift4G

Benign

0.62

T;T

Polyphen

0.043

B;B

Vest4

0.21

MutPred

0.47

Gain of methylation at K125 (P = 0.0377);Gain of methylation at K125 (P = 0.0377);

MVP

0.45

MPC

0.30

ClinPred

0.17

GERP RS

2.3

Varity_R

0.087

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over