2-152098962-G-C

Position:

• chr2-152098962-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000726.5(CACNB4):​c.50C>G​(p.Ser17Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNB4 NM_000726.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.26

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23213577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB4	NM_000726.5	c.50C>G	p.Ser17Cys	missense_variant	1/14	ENST00000539935.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB4	ENST00000539935.7	c.50C>G	p.Ser17Cys	missense_variant	1/14	1	NM_000726.5
	ENST00000420365.1	n.120+515G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

Genetic Services Laboratory, University of Chicago

Nov 21, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	0.0073	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T;.;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.34	N;.;.;N
MutationTaster	Benign	0.59	N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.88	N;.;.;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.012	D;.;.;T
Sift4G	Uncertain	0.026	D;.;.;D
Polyphen		0.19	B;.;.;.
Vest4		0.47
MutPred		0.17		Loss of glycosylation at S17 (P = 0.0059);Loss of glycosylation at S17 (P = 0.0059);Loss of glycosylation at S17 (P = 0.0059);Loss of glycosylation at S17 (P = 0.0059);
MVP		0.82
MPC		0.76
ClinPred		0.39	T
GERP RS		3.7
Varity_R		0.24
gMVP		0.38

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs797045425; hg19: chr2-152955476;