12-48824345-A-G

Variant names:

• chr12-48824345-A-G
• NM_000725.4:c.379A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/22 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
• Publications: 0 publications found

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

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=0.2882845).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000725.4. 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
	CACNB3	NM_000725.4	MANE Select	c.379A>G	p.Ile127Val	missense	Exon 4 of 13	NP_000716.2
	CACNB3	NM_001206916.2		c.376A>G	p.Ile126Val	missense	Exon 4 of 13	NP_001193845.1	P54284-4
	CACNB3	NM_001206917.2		c.340A>G	p.Ile114Val	missense	Exon 4 of 13	NP_001193846.1	P54284-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB3	ENST00000301050.7	TSL:1 MANE Select	c.379A>G	p.Ile127Val	missense	Exon 4 of 13	ENSP00000301050.2	P54284-1
	CACNB3	ENST00000536187.6	TSL:2	c.376A>G	p.Ile126Val	missense	Exon 4 of 13	ENSP00000444160.2	P54284-4
	CACNB3	ENST00000861431.1		c.379A>G	p.Ile127Val	missense	Exon 4 of 13	ENSP00000531490.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 85106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1110812

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.60	N
PhyloP100		6.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.26
Sift	Benign	0.085	T
Sift4G	Benign	0.12	T
Polyphen		0.0050	B
Vest4		0.23
MutPred		0.33		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
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

hg19: chr12-49218128;