2-151880866-G-T

Position:

• chr2-151880866-G-T

Variant summary

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

The NM_000726.5(CACNB4):​c.324C>A​(p.Asp108Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D108D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNB4 NM_000726.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.74

Genes affected

CACNB4 (HGNC:1404): (calcium voltage-gated channel auxiliary subunit beta 4) This gene encodes a member of the beta subunit family of voltage-dependent calcium channel complex proteins. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. Various versions of each of these subunits exist, either expressed from similar genes or the result of alternative splicing. The protein encoded by this locus plays an important role in calcium channel function by modulating G protein inhibition, increasing peak calcium current, controlling the alpha-1 subunit membrane targeting and shifting the voltage dependence of activation and inactivation. Certain mutations in this gene have been associated with idiopathic generalized epilepsy (IGE), juvenile myoclonic epilepsy (JME), and episodic ataxia, type 5. [provided by RefSeq, Aug 2016]

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=0.30934584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB4	NM_000726.5	c.324C>A	p.Asp108Glu	missense_variant	4/14	ENST00000539935.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB4	ENST00000539935.7	c.324C>A	p.Asp108Glu	missense_variant	4/14	1	NM_000726.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	1.1
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D;.;.;T;T;.;T;T;.;.;T;T;.;.;T;.;.;T;.;T;T;T;.;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.059	N
LIST_S2	Uncertain	0.87	D;D;D;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.1	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.8	N;.;.;.;.;.;.;.;.;.;.;.;.;N;.;N;.;.;.;.;.;N;N;.;.;.
REVEL	Uncertain	0.51
Sift	Benign	0.34	T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.;T;T;.;.;.
Sift4G	Benign	0.23	T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.;T;T;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.62
MutPred		0.35		Gain of disorder (P = 0.1718);.;.;.;.;Gain of disorder (P = 0.1718);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of disorder (P = 0.1718);.;.;.;
MVP		0.71
MPC		0.62
ClinPred		0.71	D
GERP RS		-10
Varity_R		0.16
gMVP		0.70

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

Other links and lift over

dbSNP: rs147647355; hg19: chr2-152737380;