rs199525864

Variant names:

• chr9-138120371-C-T
• rs199525864
• NM_000718.4:c.6237C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

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
• Publications: 2 publications found

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]

CACNA1B Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
• complex neurodevelopmental disorder with motor features

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000718.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1B	NM_000718.4	MANE Select	c.6237C>T	p.Gly2079Gly	splice_region synonymous	Exon 45 of 47	NP_000709.1	Q00975-1
	CACNA1B	NM_001243812.2		c.6237C>T	p.Gly2079Gly	splice_region synonymous	Exon 45 of 47	NP_001230741.1	Q00975-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1B	ENST00000371372.6	TSL:5 MANE Select	c.6237C>T	p.Gly2079Gly	splice_region synonymous	Exon 45 of 47	ENSP00000360423.1	Q00975-1
	CACNA1B	ENST00000371357.5	TSL:5	c.6234C>T	p.Gly2078Gly	splice_region synonymous	Exon 44 of 46	ENSP00000360408.1	B1AQK7
	CACNA1B	ENST00000371363.5	TSL:5	c.6231C>T	p.Gly2077Gly	splice_region synonymous	Exon 44 of 46	ENSP00000360414.1	B1AQK6

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

GnomAD2 exomes AF: 0.000276 AC: 42 AN: 152028 AF XY: 0.000230

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 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

African (AFR) AF: 0.00 AC: 0 AN: 32132

American (AMR) AF: 0.000107 AC: 4 AN: 37228

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 29 AN: 25268

East Asian (EAS) AF: 0.0000274 AC: 1 AN: 36546

South Asian (SAS) AF: 0.00 AC: 0 AN: 79890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36824

Middle Eastern (MID) AF: 0.000229 AC: 1 AN: 4364

European-Non Finnish (NFE) AF: 0.000276 AC: 300 AN: 1085354

Other (OTH) AF: 0.000189 AC: 11 AN: 58236

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

African (AFR) AF: 0.0000482 AC: 2 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68018

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000274 Hom.: 0

Bravo AF: 0.000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.64
DANN	Benign	0.26
PhyloP100		-3.3
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs199525864; hg19: chr9-141014823;