NM_000725.4:c.421C>A

Variant names:

• chr12-48824682-C-A
• rs779429114
• NM_000725.4:c.421C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000725.4(CACNB3):​c.421C>A​(p.Pro141Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,648 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. 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. P141A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNB3 NM_000725.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15873456).

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.421C>A	p.Pro141Thr	missense	Exon 5 of 13	NP_000716.2
	CACNB3	NM_001206916.2		c.418C>A	p.Pro140Thr	missense	Exon 5 of 13	NP_001193845.1	P54284-4
	CACNB3	NM_001206917.2		c.382C>A	p.Pro128Thr	missense	Exon 5 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.421C>A	p.Pro141Thr	missense	Exon 5 of 13	ENSP00000301050.2	P54284-1
	CACNB3	ENST00000536187.6	TSL:2	c.418C>A	p.Pro140Thr	missense	Exon 5 of 13	ENSP00000444160.2	P54284-4
	CACNB3	ENST00000861431.1		c.418C>A	p.Pro140Thr	missense	Exon 5 of 13	ENSP00000531490.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151874 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461774 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111920

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151874 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74154

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000242 AC: 1 AN: 41314

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.24
Eigen_PC	Benign	0.0095
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.49	N
PhyloP100		1.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.21
Sift	Uncertain	0.029	D
Sift4G	Benign	0.11	T
Polyphen		0.28	B
Vest4		0.17
MutPred		0.38		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.78
MPC		0.52
ClinPred		0.40	T
GERP RS		4.8
Varity_R		0.088
gMVP		0.39
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

dbSNP: rs779429114; hg19: chr12-49218465;