NM_000718.4:c.79G>A

Variant names:

• chr9-137878012-G-A
• rs758563303
• NM_000718.4:c.79G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000718.4(CACNA1B):​c.79G>A​(p.Gly27Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000667 in 149,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G27C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1B NM_000718.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• Publications: 0 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

CACNA1B-AS2 (HGNC:58213):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31226534).

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.79G>A	p.Gly27Ser	missense	Exon 1 of 47	NP_000709.1	Q00975-1
	CACNA1B	NM_001243812.2		c.79G>A	p.Gly27Ser	missense	Exon 1 of 47	NP_001230741.1	Q00975-2
	CACNA1B-AS2	NR_121583.1		n.2692-2332C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1B	ENST00000371372.6	TSL:5 MANE Select	c.79G>A	p.Gly27Ser	missense	Exon 1 of 47	ENSP00000360423.1	Q00975-1
	CACNA1B	ENST00000371357.5	TSL:5	c.79G>A	p.Gly27Ser	missense	Exon 1 of 46	ENSP00000360408.1	B1AQK7
	CACNA1B	ENST00000371363.5	TSL:5	c.79G>A	p.Gly27Ser	missense	Exon 1 of 46	ENSP00000360414.1	B1AQK6

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149960 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1079684 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 516574

African (AFR) AF: 0.00 AC: 0 AN: 21480

American (AMR) AF: 0.00 AC: 0 AN: 7680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13040

East Asian (EAS) AF: 0.00 AC: 0 AN: 22560

South Asian (SAS) AF: 0.00 AC: 0 AN: 23444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3642

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 913184

Other (OTH) AF: 0.00 AC: 0 AN: 41548

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149960 Hom.: 0 Cov.: 34 AF XY: 0.0000137 AC XY: 1 AN XY: 73106

African (AFR) AF: 0.00 AC: 0 AN: 41172

American (AMR) AF: 0.00 AC: 0 AN: 15070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67196

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.35
Sift	Benign	0.28	T
Sift4G	Benign	0.61	T
Polyphen		0.052	B
Vest4		0.42
MutPred		0.33		Gain of glycosylation at G27 (P = 0.0016)
MVP		0.80
MPC		1.5
ClinPred		0.64	D
GERP RS		0.65
PromoterAI		-0.014	Neutral
Varity_R		0.062
gMVP		0.30
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs758563303; hg19: chr9-140772464;