10-18498401-C-G

Variant names:

• chr10-18498401-C-G
• rs200367454
• NM_201596.3:c.380C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_201596.3(CACNB2):​c.380C>G​(p.Ala127Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. A127V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CACNB2 NM_201596.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.95
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome 4

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• cardiogenetic disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1799382).
• BS2: High AC in GnomAdExome4 at 10 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201596.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	NM_201596.3	MANE Select	c.380C>G	p.Ala127Gly	missense	Exon 4 of 14	NP_963890.2	Q08289-1
	CACNB2	NM_201590.3	MANE Plus Clinical	c.218C>G	p.Ala73Gly	missense	Exon 3 of 13	NP_963884.2	Q08289-3
	CACNB2	NM_201597.3		c.380C>G	p.Ala127Gly	missense	Exon 4 of 14	NP_963891.1	Q08289-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNB2	ENST00000324631.13	TSL:1 MANE Select	c.380C>G	p.Ala127Gly	missense	Exon 4 of 14	ENSP00000320025.8	Q08289-1
	CACNB2	ENST00000377329.10	TSL:1 MANE Plus Clinical	c.218C>G	p.Ala73Gly	missense	Exon 3 of 13	ENSP00000366546.4	Q08289-3
	CACNB2	ENST00000352115.10	TSL:1	c.380C>G	p.Ala127Gly	missense	Exon 4 of 14	ENSP00000344474.6	Q08289-8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251320 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461710 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727172

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111862

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	-1.1	N
PhyloP100		4.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	1.7	N
REVEL	Uncertain	0.48
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.30
MutPred		0.38		Gain of glycosylation at S126 (P = 0.0502)
MVP		0.83
MPC		0.28
ClinPred		0.58	D
GERP RS		5.7
Varity_R		0.15
gMVP		0.36
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs200367454; hg19: chr10-18787330;