10-18515022-G-C

Position:

• chr10-18515022-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_201597.3(CACNB2):​c.713G>C​(p.Gly238Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/15 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. G238D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CACNB2 NM_201597.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14028025).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.804+653G>C		intron_variant		ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.642+653G>C		intron_variant		ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.804+653G>C		intron_variant		1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.642+653G>C		intron_variant		1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251154 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135720

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461446 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727064

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.73
DEOGEN2	Benign	0.0029	.;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.051
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.58	T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.64	T
PROVEAN	Benign	0.13	N;.;.
REVEL	Benign	0.26
Sift	Benign	0.77	T;.;.
Sift4G	Benign	0.49	T;.;T
Polyphen		0.0	B;.;.
Vest4		0.14
MutPred		0.33		Gain of sheet (P = 0.0344);.;.;
MVP		0.75
ClinPred		0.11	T
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs142899184; hg19: chr10-18803951;