12-2004298-T-A

Position:

• chr12-2004298-T-A

Variant summary

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

The NM_152640.5(DCP1B):​c.134A>T​(p.His45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCP1B NM_152640.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12

Genes affected

DCP1B (HGNC:24451): (decapping mRNA 1B) This gene encodes a member of a family of proteins that function in removing the 5' cap from mRNAs, which is a step in regulated mRNA decay. This protein localizes to cytoplasmic foci which are the site of mRNA breakdown and turnover. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

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	Protein	UniProt
DCP1B	NM_152640.5	c.134A>T	p.His45Leu	missense_variant	1/9	ENST00000280665.11	NP_689853.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCP1B	ENST00000280665.11	c.134A>T	p.His45Leu	missense_variant	1/9	1	NM_152640.5	ENSP00000280665.6
CACNA1C	ENST00000682544.1	c.139+33097T>A		intron_variant				ENSP00000507184.1
CACNA1C	ENST00000683824.1	c.139+33097T>A		intron_variant				ENSP00000507867.1
CACNA1C	ENST00000682462.1	c.139+33097T>A		intron_variant				ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.139+33097T>A		intron_variant				ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.139+33097T>A		intron_variant				ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.139+33097T>A		intron_variant				ENSP00000506882.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Aug 21, 2024

The c.134A>T (p.H45L) alteration is located in exon 1 (coding exon 1) of the DCP1B gene. This alteration results from a A to T substitution at nucleotide position 134, causing the histidine (H) at amino acid position 45 to be replaced by a leucine (L). 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.066	T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.096	N
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Benign	0.17
Sift	Benign	0.090	T;.
Sift4G	Benign	0.088	T;T
Polyphen		1.0	D;P
Vest4		0.52
MutPred		0.61		Gain of catalytic residue at R46 (P = 0.0126);Gain of catalytic residue at R46 (P = 0.0126);
MVP		0.37
MPC		0.27
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1401092613; hg19: chr12-2113464;