chr2-152098962-G-A

Position:

• chr2-152098962-G-A

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>T​(p.Ser17Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000729 in 1,372,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S17C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CACNB4 NM_000726.5 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.236321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB4	NM_000726.5	c.50C>T	p.Ser17Phe	missense_variant	1/14	ENST00000539935.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB4	ENST00000539935.7	c.50C>T	p.Ser17Phe	missense_variant	1/14	1	NM_000726.5
	ENST00000420365.1	n.120+515G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1372278 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 676482

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: 9.35e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T;.;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.34	N;.;.;N
MutationTaster	Benign	0.70	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.92	N;.;.;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	D;.;.;D
Sift4G	Uncertain	0.025	D;.;.;D
Polyphen		0.19	B;.;.;.
Vest4		0.46
MutPred		0.20		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		0.83
MPC		0.79
ClinPred		0.65	D
GERP RS		3.7
Varity_R		0.26
gMVP		0.34

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;