9-137877963-C-T

Position:

• chr9-137877963-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000718.4(CACNA1B):​c.30C>T​(p.Gly10=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,101,120 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 0.0031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (1 hom.)
• Consequence: CACNA1B NM_000718.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.66

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 9-137877963-C-T is Benign according to our data. Variant chr9-137877963-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 374676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137877963-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00315 (468/148754) while in subpopulation NFE AF= 0.0048 (320/66674). AF 95% confidence interval is 0.00437. There are 0 homozygotes in gnomad4. There are 202 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 468 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1B	NM_000718.4	c.30C>T	p.Gly10=	synonymous_variant	1/47	ENST00000371372.6	NP_000709.1
LOC100133077	NR_121583.1	n.2692-2283G>A		intron_variant, non_coding_transcript_variant
CACNA1B	NM_001243812.2	c.30C>T	p.Gly10=	synonymous_variant	1/47		NP_001230741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1B	ENST00000371372.6	c.30C>T	p.Gly10=	synonymous_variant	1/47	5	NM_000718.4	ENSP00000360423	P4
	ENST00000371390.1	n.2692-2283G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 471 AN: 148652 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00481

Gnomad ASJ AF: 0.00117

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.000213

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.00481

Gnomad OTH AF: 0.00293

GnomAD4 exome AF: 0.00451 AC: 4298 AN: 952366 Hom.: 1 Cov.: 23 AF XY: 0.00445 AC XY: 1992 AN XY: 448050

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00921

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00389

Gnomad4 FIN exome AF: 0.000930

Gnomad4 NFE exome AF: 0.00475

Gnomad4 OTH exome AF: 0.00380

GnomAD4 genome AF: 0.00315 AC: 468 AN: 148754 Hom.: 0 Cov.: 33 AF XY: 0.00278 AC XY: 202 AN XY: 72534

Gnomad4 AFR AF: 0.00114

Gnomad4 AMR AF: 0.00467

Gnomad4 ASJ AF: 0.00117

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.000213

Gnomad4 NFE AF: 0.00480

Gnomad4 OTH AF: 0.00290

Alfa AF: 0.00300 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CACNA1B: BP4, BP7 -

CACNA1B-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2024

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.95

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: rs767457983; hg19: chr9-140772415;