rs200297403

chr10-18539299-C-Achr10-18539299-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_201596.3(CACNB2):c.1558C>A(p.Pro520Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 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. P520L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Not reported in ClinVar
• 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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042607248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNB2	NM_201596.3	c.1558C>A	p.Pro520Thr	missense_variant	14/14	ENST00000324631.13
CACNB2	NM_201590.3	c.1396C>A	p.Pro466Thr	missense_variant	13/13	ENST00000377329.10
LOC124902386	XR_007062076.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNB2	ENST00000324631.13	c.1558C>A	p.Pro520Thr	missense_variant	14/14	1	NM_201596.3
CACNB2	ENST00000377329.10	c.1396C>A	p.Pro466Thr	missense_variant	13/13	1	NM_201590.3
	ENST00000425669.1	n.377G>T		splice_region_variant, non_coding_transcript_exon_variant	4/5	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251410 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	2.8
Dann	Benign	0.84
DEOGEN2	Benign	0.10	T;.;T;.;.;.;T;T;.;.;.;T;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.89	D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.043	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.14	N;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.93	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.60	N;N;N;.;.;N;.;.;N;N;N;.;N;N
REVEL	Benign	0.087
Sift	Benign	0.26	T;T;T;.;.;T;.;.;T;T;T;.;T;T
Sift4G	Benign	0.52	T;T;T;.;.;T;T;T;T;T;T;T;T;.
Polyphen		0.0	B;B;B;.;.;B;.;.;.;B;B;.;.;.
Vest4		0.040
MutPred		0.15		Gain of phosphorylation at P520 (P = 0.0399);.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.85
MPC		0.23
ClinPred		0.027	T
GERP RS		4.0
Varity_R		0.047
gMVP		0.23

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;