chr9-137877982-G-A

Variant names:

• chr9-137877982-G-A
• rs187204220
• NM_000718.4:c.49G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000718.4(CACNA1B):​c.49G>A​(p.Gly17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,130,022 control chromosomes in the GnomAD database, including 2,903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (728 hom., cov: 33)
  • Exomes 𝑓: 0.16 (2175 hom.)
• Consequence: CACNA1B NM_000718.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.09
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010201633).
• BP6: Variant 9-137877982-G-A is Benign according to our data. Variant chr9-137877982-G-A is described in ClinVar as Benign. ClinVar VariationId is 1222494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

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.49G>A	p.Gly17Ser	missense	Exon 1 of 47	NP_000709.1	Q00975-1
	CACNA1B	NM_001243812.2		c.49G>A	p.Gly17Ser	missense	Exon 1 of 47	NP_001230741.1	Q00975-2
	CACNA1B-AS2	NR_121583.1		n.2692-2302C>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.49G>A	p.Gly17Ser	missense	Exon 1 of 47	ENSP00000360423.1	Q00975-1
	CACNA1B	ENST00000371357.5	TSL:5	c.49G>A	p.Gly17Ser	missense	Exon 1 of 46	ENSP00000360408.1	B1AQK7
	CACNA1B	ENST00000371363.5	TSL:5	c.49G>A	p.Gly17Ser	missense	Exon 1 of 46	ENSP00000360414.1	B1AQK6

Frequencies

GnomAD3 genomes AF: 0.134 AC: 19969 AN: 148528 Hom.: 732 Cov.: 33

Gnomad AFR AF: 0.0856

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.00471

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.112

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.120 AC: 1260 AN: 10516 AF XY: 0.119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.156 AC: 152903 AN: 981384 Hom.: 2175 Cov.: 29 AF XY: 0.157 AC XY: 72604 AN XY: 463456

African (AFR) AF: 0.0819 AC: 1579 AN: 19270

American (AMR) AF: 0.199 AC: 1093 AN: 5484

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 1975 AN: 10216

East Asian (EAS) AF: 0.00358 AC: 56 AN: 15660

South Asian (SAS) AF: 0.140 AC: 2591 AN: 18448

European-Finnish (FIN) AF: 0.178 AC: 4136 AN: 23222

Middle Eastern (MID) AF: 0.135 AC: 343 AN: 2546

European-Non Finnish (NFE) AF: 0.160 AC: 135646 AN: 849902

Other (OTH) AF: 0.150 AC: 5484 AN: 36636

GnomAD4 genome AF: 0.134 AC: 19966 AN: 148638 Hom.: 728 Cov.: 33 AF XY: 0.134 AC XY: 9720 AN XY: 72486

African (AFR) AF: 0.0855 AC: 3516 AN: 41124

American (AMR) AF: 0.167 AC: 2493 AN: 14960

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 547 AN: 3414

East Asian (EAS) AF: 0.00473 AC: 24 AN: 5078

South Asian (SAS) AF: 0.139 AC: 666 AN: 4786

European-Finnish (FIN) AF: 0.154 AC: 1459 AN: 9474

Middle Eastern (MID) AF: 0.113 AC: 33 AN: 292

European-Non Finnish (NFE) AF: 0.162 AC: 10793 AN: 66544

Other (OTH) AF: 0.129 AC: 267 AN: 2062

Alfa AF: 0.155 Hom.: 80

ExAC AF: 0.0562 AC: 229

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CACNA1B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0010	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.34
Sift	Benign	0.49	T
Sift4G	Benign	0.35	T
Polyphen		0.13	B
Vest4		0.12
MPC		1.5
ClinPred		0.031	T
GERP RS		2.6
PromoterAI		-0.032	Neutral
Varity_R		0.053
gMVP		0.33
Mutation Taster		=94/6	polymorphism (auto)

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: rs187204220; hg19: chr9-140772434; COSMIC: COSV53132412; COSMIC: COSV53132412;