Genetic Variant CACNB2:p.Pro520Ser (chr10-18539299-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_201596.3(CACNB2):c.1558C>T(p.Pro520Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P520P) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CACNB2
NM_201596.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.335

Variant links:

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]

CACNB2 links:

ENSG00000240291 (HGNC:58168):

ENSG00000240291 links:

LOC124902386 (HGNC:):

LOC124902386 links:

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ACMG classification

Classification made for transcript

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=0.04176429).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3 link	c.1558C>T	p.Pro520Ser	missense_variant	Exon 14 of 14	ENST00000324631.13	NP_963890.2	Q08289-1
CACNB2	NM_201590.3 link	c.1396C>T	p.Pro466Ser	missense_variant	Exon 13 of 13	ENST00000377329.10	NP_963884.2	Q08289-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13 link	c.1558C>T	p.Pro520Ser	missense_variant	Exon 14 of 14	1	NM_201596.3	ENSP00000320025.8		Q08289-1
CACNB2	ENST00000377329.10 link	c.1396C>T	p.Pro466Ser	missense_variant	Exon 13 of 13	1	NM_201590.3	ENSP00000366546.4		Q08289-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727224

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

3.1

DANN

Benign

0.82

DEOGEN2

Benign

0.11

T;.;T;.;.;.;T;T;.;.;.;T;.;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.87

D;D;D;.;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.042

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.0

N;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.080

N;N;N;.;.;N;.;.;N;N;N;.;N;N

REVEL

Benign

0.061

Sift

Benign

0.54

T;T;T;.;.;T;.;.;T;T;T;.;T;T

Sift4G

Benign

0.71

T;T;T;.;.;T;T;T;T;T;T;T;T;.

Polyphen

0.036

B;B;P;.;.;B;.;.;.;B;B;.;.;.

Vest4

0.063

MutPred

0.20

Gain of phosphorylation at P520 (P = 0.0063);.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.84

MPC

0.21

ClinPred

0.021

GERP RS

4.0

Varity_R

0.032

gMVP

0.21

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over