10-18539299-C-G

Variant names:

• chr10-18539299-C-G
• rs200297403
• NM_201596.3:c.1558C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_201596.3(CACNB2):​c.1558C>G​(p.Pro520Ala) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P520P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.335

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]

ENSG00000240291 (HGNC:58168):

LOC124902386 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035467744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.1558C>G	p.Pro520Ala	missense_variant	Exon 14 of 14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.1396C>G	p.Pro466Ala	missense_variant	Exon 13 of 13	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.1558C>G	p.Pro520Ala	missense_variant	Exon 14 of 14	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.1396C>G	p.Pro466Ala	missense_variant	Exon 13 of 13	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.64
DANN	Benign	0.49
DEOGEN2	Benign	0.13	T;.;T;.;.;.;T;T;.;.;.;T;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.86	D;D;T;.;D;D;T;D;D;D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.035	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.20	N;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.15	N;N;N;.;.;N;.;.;N;N;N;.;N;N
REVEL	Benign	0.070
Sift	Benign	0.78	T;T;T;.;.;T;.;.;T;T;T;.;T;T
Sift4G	Benign	0.74	T;T;T;.;.;T;T;T;T;T;T;T;T;.
Polyphen		0.0	B;B;B;.;.;B;.;.;.;B;B;.;.;.
Vest4		0.066
MutPred		0.22		Loss of loop (P = 0.0288);.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.83
MPC		0.20
ClinPred		0.015	T
GERP RS		4.0
Varity_R		0.029
gMVP		0.17

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: rs200297403; hg19: chr10-18828228;