12-48818934-A-T

Position:

• chr12-48818934-A-T

Variant summary

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

The NM_000725.4(CACNB3):​c.5A>T​(p.Tyr2Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,445,298 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNB3 NM_000725.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB3	NM_000725.4	c.5A>T	p.Tyr2Phe	missense_variant	1/13	ENST00000301050.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB3	ENST00000301050.7	c.5A>T	p.Tyr2Phe	missense_variant	1/13	1	NM_000725.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445298 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 717628

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: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Ambry Genetics

Jun 07, 2023

The c.5A>T (p.Y2F) alteration is located in exon 1 (coding exon 1) of the CACNB3 gene. This alteration results from a A to T substitution at nucleotide position 5, causing the tyrosine (Y) at amino acid position 2 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.088	.;T;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.4	.;L;.;L
MutationTaster	Benign	0.94	D;D;D;D;D
PROVEAN	Benign	-0.59	N;N;N;N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.18	T;T;T;D
Polyphen		0.88	.;P;.;.
Vest4		0.41
MutPred		0.23		Loss of phosphorylation at Y2 (P = 0.0088);Loss of phosphorylation at Y2 (P = 0.0088);Loss of phosphorylation at Y2 (P = 0.0088);Loss of phosphorylation at Y2 (P = 0.0088);
MVP		0.80
MPC		0.39
ClinPred		0.78	D
GERP RS		3.5
Varity_R		0.31
gMVP		0.33

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: rs759686097; hg19: chr12-49212717;