9-137877982-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000718.4(CACNA1B):c.49G>A(p.Gly17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,130,022 control chromosomes in the GnomAD database, including 2,903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (728 hom., cov: 33)
  • Exomes 𝑓: 0.16 (2175 hom.)
• Consequence: CACNA1B NM_000718.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.09

Genes affected

CACNA1B (HGNC:1389): (calcium voltage-gated channel subunit alpha1 B) The protein encoded by this gene is the pore-forming subunit of an N-type voltage-dependent calcium channel, which controls neurotransmitter release from neurons. The encoded protein forms a complex with alpha-2, beta, and delta subunits to form the high-voltage activated channel. This channel is sensitive to omega-conotoxin-GVIA and omega-agatoxin-IIIA but insensitive to dihydropyridines. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CACNA1B
• BP4: Computational evidence support a benign effect (MetaRNN=0.0010201633).
• BP6: Variant 9-137877982-G-A is Benign according to our data. Variant chr9-137877982-G-A is described in ClinVar as [Benign]. Clinvar id is 1222494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1B	NM_000718.4	c.49G>A	p.Gly17Ser	missense_variant	1/47	ENST00000371372.6
LOC100133077	NR_121583.1	n.2692-2302C>T		intron_variant, non_coding_transcript_variant
CACNA1B	NM_001243812.2	c.49G>A	p.Gly17Ser	missense_variant	1/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1B	ENST00000371372.6	c.49G>A	p.Gly17Ser	missense_variant	1/47	5	NM_000718.4	P4
	ENST00000371390.1	n.2692-2302C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.134 AC: 19969 AN: 148528 Hom.: 732 Cov.: 33

Gnomad AFR AF: 0.0856

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.00471

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.112

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.120 AC: 1260 AN: 10516 Hom.: 0 AF XY: 0.119 AC XY: 626 AN XY: 5240

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.167

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.156 AC: 152903 AN: 981384 Hom.: 2175 Cov.: 29 AF XY: 0.157 AC XY: 72604 AN XY: 463456

Gnomad4 AFR exome AF: 0.0819

Gnomad4 AMR exome AF: 0.199

Gnomad4 ASJ exome AF: 0.193

Gnomad4 EAS exome AF: 0.00358

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.134 AC: 19966 AN: 148638 Hom.: 728 Cov.: 33 AF XY: 0.134 AC XY: 9720 AN XY: 72486

Gnomad4 AFR AF: 0.0855

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.00473

Gnomad4 SAS AF: 0.139

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.129

Alfa AF: 0.155 Hom.: 80

ExAC AF: 0.0562 AC: 229

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 31, 2019

- -

CACNA1B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	20
Dann	Uncertain	0.98
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.64	T;T;T;T;T;T
MetaRNN	Benign	0.0010	T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.3	L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.2	N;N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.49	T;T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T;T
Polyphen		0.13	.;.;.;B;.;.
Vest4		0.12
MPC		1.5
ClinPred		0.031	T
GERP RS		2.6
Varity_R		0.053
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs187204220; hg19: chr9-140772434; COSMIC: COSV53132412; COSMIC: COSV53132412;