9-137878025-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000718.4(CACNA1B):c.92G>T(p.Gly31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 150,358 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00017 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1B NM_000718.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.854

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=0.0054852366).
• BP6: Variant 9-137878025-G-T is Benign according to our data. Variant chr9-137878025-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1317163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137878025-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00436 (655/150358) while in subpopulation AFR AF= 0.0147 (607/41326). AF 95% confidence interval is 0.0137. There are 1 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 657 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1B	NM_000718.4	c.92G>T	p.Gly31Val	missense_variant	1/47	ENST00000371372.6
LOC100133077	NR_121583.1	n.2692-2345C>A		intron_variant, non_coding_transcript_variant
CACNA1B	NM_001243812.2	c.92G>T	p.Gly31Val	missense_variant	1/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1B	ENST00000371372.6	c.92G>T	p.Gly31Val	missense_variant	1/47	5	NM_000718.4	P4
	ENST00000371390.1	n.2692-2345C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 657 AN: 150250 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00192

Gnomad ASJ AF: 0.000580

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00486

GnomAD3 exomes AF: 0.0122 AC: 748 AN: 61328 Hom.: 1 AF XY: 0.0120 AC XY: 423 AN XY: 35120

Gnomad AFR exome AF: 0.0224

Gnomad AMR exome AF: 0.00850

Gnomad ASJ exome AF: 0.00990

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0115

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0145

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000166 AC: 186 AN: 1118290 Hom.: 1 Cov.: 32 AF XY: 0.000159 AC XY: 86 AN XY: 539428

Gnomad4 AFR exome AF: 0.00476

Gnomad4 AMR exome AF: 0.00120

Gnomad4 ASJ exome AF: 0.000131

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000428

Gnomad4 OTH exome AF: 0.000573

GnomAD4 genome AF: 0.00436 AC: 655 AN: 150358 Hom.: 1 Cov.: 34 AF XY: 0.00411 AC XY: 302 AN XY: 73418

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.00192

Gnomad4 ASJ AF: 0.000580

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000104

Gnomad4 OTH AF: 0.00481

Alfa AF: 0.00788 Hom.: 7

ExAC AF: 0.00221 AC: 193

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CACNA1B: PP3, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.59	T;T;T;T;T;T
MetaRNN	Benign	0.0055	T;T;T;T;T;T
MetaSVM	Uncertain	0.058	D
MutationAssessor	Benign	0.58	N;.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.1	N;.;N;N;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.025	D;.;T;T;T;T
Sift4G	Uncertain	0.022	D;D;D;D;D;D
Polyphen		0.012	.;.;.;B;.;.
Vest4		0.27
MPC		0.94
ClinPred		0.011	T
GERP RS		1.3
Varity_R		0.16
gMVP		0.38

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: rs201253748; hg19: chr9-140772477; COSMIC: COSV53138791; COSMIC: COSV53138791;