rs199525864

Positions:

• chr9-138120371-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000718.4(CACNA1B):​c.6237C>T​(p.Gly2079Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,548,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: CACNA1B NM_000718.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.002987
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -3.34

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000164 (25/152198) while in subpopulation NFE AF= 0.00025 (17/68018). AF 95% confidence interval is 0.000159. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1B	NM_000718.4	c.6237C>T	p.Gly2079Gly	splice_region_variant, synonymous_variant	45/47	ENST00000371372.6	NP_000709.1
CACNA1B	NM_001243812.2	c.6237C>T	p.Gly2079Gly	splice_region_variant, synonymous_variant	45/47		NP_001230741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1B	ENST00000371372.6	c.6237C>T	p.Gly2079Gly	splice_region_variant, synonymous_variant	45/47	5	NM_000718.4	ENSP00000360423.1
CACNA1B	ENST00000371357.5	c.6234C>T	p.Gly2078Gly	splice_region_variant, synonymous_variant	44/46	5		ENSP00000360408.1
CACNA1B	ENST00000371363.5	c.6231C>T	p.Gly2077Gly	splice_region_variant, synonymous_variant	44/46	5		ENSP00000360414.1
CACNA1B	ENST00000277551.6	c.6237C>T	p.Gly2079Gly	splice_region_variant, synonymous_variant	45/47	5		ENSP00000277551.2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000276 AC: 42 AN: 152028 Hom.: 0 AF XY: 0.000230 AC XY: 19 AN XY: 82584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.000399

Gnomad OTH exome AF: 0.000905

GnomAD4 exome AF: 0.000248 AC: 346 AN: 1395842 Hom.: 0 Cov.: 32 AF XY: 0.000225 AC XY: 155 AN XY: 690122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000107

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.0000274

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000276

Gnomad4 OTH exome AF: 0.000189

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74348

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000291 Hom.: 0

Bravo AF: 0.000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change affects codon 2079 of the CACNA1B mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CACNA1B protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CACNA1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 377312). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 28, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2022	Has not been previously published as pathogenic or benign in association with neurodevelopmental disorders to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28719003, 26740555) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.64
DANN	Benign	0.26

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0030
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199525864; hg19: chr9-141014823;