12-48824345-A-G

Position:

• chr12-48824345-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000725.4(CACNB3):​c.379A>G​(p.Ile127Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000549 in 1,458,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CACNB3 NM_000725.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25

Genes affected

CACNB3 (HGNC:1403): (calcium voltage-gated channel auxiliary subunit beta 3) This gene encodes a regulatory beta subunit of the voltage-dependent calcium channel. Beta subunits are composed of five domains, which contribute to the regulation of surface expression and gating of calcium channels and may also play a role in the regulation of transcription factors and calcium transport. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2882845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB3	NM_000725.4	c.379A>G	p.Ile127Val	missense_variant	4/13	ENST00000301050.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB3	ENST00000301050.7	c.379A>G	p.Ile127Val	missense_variant	4/13	1	NM_000725.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1458342 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 724942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Feb 28, 2023

The c.379A>G (p.I127V) alteration is located in exon 4 (coding exon 4) of the CACNB3 gene. This alteration results from a A to G substitution at nucleotide position 379, causing the isoleucine (I) at amino acid position 127 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	0.089
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;.;.;T;.;.
Eigen	Benign	0.021
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.29	T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.60	.;.;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.53	N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.085	T;T;D;T;T;D
Sift4G	Benign	0.12	T;T;T;T;T;T
Polyphen		0.0050	.;.;.;B;.;.
Vest4		0.23
MutPred		0.33		.;.;Gain of catalytic residue at R123 (P = 0.0084);Gain of catalytic residue at R123 (P = 0.0084);.;.;
MVP		0.60
MPC		0.36
ClinPred		0.71	D
GERP RS		4.2
Varity_R		0.065
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-49218128;