10-18500899-A-T

Variant summary

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

The NM_201596.3(CACNB2):c.544A>T(p.Met182Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. M182V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.46

Genes affected

CACNB2 (HGNC:1402): (calcium voltage-gated channel auxiliary subunit beta 2) This gene encodes a subunit of a voltage-dependent calcium channel protein that is a member of the voltage-gated calcium channel superfamily. The gene product was originally identified as an antigen target in Lambert-Eaton myasthenic syndrome, an autoimmune disorder. Mutations in this gene are associated with Brugada syndrome. Alternatively spliced variants encoding different isoforms have been described. [provided by RefSeq, Feb 2013]

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=0.24806586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB2	NM_201596.3	c.544A>T	p.Met182Leu	missense_variant	5/14	ENST00000324631.13
CACNB2	NM_201590.3	c.382A>T	p.Met128Leu	missense_variant	4/13	ENST00000377329.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB2	ENST00000324631.13	c.544A>T	p.Met182Leu	missense_variant	5/14	1	NM_201596.3
CACNB2	ENST00000377329.10	c.382A>T	p.Met128Leu	missense_variant	4/13	1	NM_201590.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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 Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	21
Dann	Benign	0.92
DEOGEN2	Benign	0.067	T;.;.;.;.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	0.024
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;.;D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-0.20	N;N;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.25	N;N;.;.;N;.;N;N;N;.;N;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.82	T;T;.;.;T;.;T;T;T;.;T;.;.
Sift4G	Benign	0.81	T;T;.;.;T;T;T;T;T;T;T;.;.
Polyphen		0.0080	B;B;.;.;B;.;.;B;B;B;.;.;.
Vest4		0.42
MutPred		0.28		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);.;.;.;.;.;.;.;.;.;.;.;
MVP		0.67
MPC		0.19
ClinPred		0.84	D
GERP RS		5.9
Varity_R		0.36
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs775466397; hg19: chr10-18789828;