22-39570958-G-A

Position:

• chr22-39570958-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021096.4(CACNA1I):​c.206G>A​(p.Arg69Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1I NM_021096.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.35

Genes affected

CACNA1I (HGNC:1396): (calcium voltage-gated channel subunit alpha1 I) This gene encodes the pore-forming alpha subunit of a voltage gated calcium channel. The encoded protein is a member of a subfamily of calcium channels referred to as is a low voltage-activated, T-type, calcium channel. The channel encoded by this protein is characterized by a slower activation and inactivation compared to other T-type calcium channels. This protein may be involved in calcium signaling in neurons. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1I	NM_021096.4	c.206G>A	p.Arg69Gln	missense_variant	1/37	ENST00000402142.4	NP_066919.2
CACNA1I	NM_001003406.2	c.206G>A	p.Arg69Gln	missense_variant	1/36		NP_001003406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1I	ENST00000402142.4	c.206G>A	p.Arg69Gln	missense_variant	1/37	1	NM_021096.4	ENSP00000385019.3
CACNA1I	ENST00000404898.5	c.206G>A	p.Arg69Gln	missense_variant	1/36	1		ENSP00000384093.1
CACNA1I	ENST00000401624.5	c.206G>A	p.Arg69Gln	missense_variant	1/36	1		ENSP00000383887.1
CACNA1I	ENST00000407673.5	c.206G>A	p.Arg69Gln	missense_variant	1/35	1		ENSP00000385680.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461630 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.206G>A (p.R69Q) alteration is located in exon 1 (coding exon 1) of the CACNA1I gene. This alteration results from a G to A substitution at nucleotide position 206, causing the arginine (R) at amino acid position 69 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	.;.;.;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.2	M;M;M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.025	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.93
MutPred		0.67		Gain of methylation at K74 (P = 0.0849);Gain of methylation at K74 (P = 0.0849);Gain of methylation at K74 (P = 0.0849);Gain of methylation at K74 (P = 0.0849);
MVP		0.98
MPC		1.0
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.32
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-39966963; COSMIC: COSV60808988;