22-39570825-C-G

Position:

• chr22-39570825-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021096.4(CACNA1I):​c.73C>G​(p.Gln25Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1I NM_021096.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23361579).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1I	NM_021096.4	c.73C>G	p.Gln25Glu	missense_variant	1/37	ENST00000402142.4	NP_066919.2
CACNA1I	NM_001003406.2	c.73C>G	p.Gln25Glu	missense_variant	1/36		NP_001003406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1I	ENST00000402142.4	c.73C>G	p.Gln25Glu	missense_variant	1/37	1	NM_021096.4	ENSP00000385019.3
CACNA1I	ENST00000404898.5	c.73C>G	p.Gln25Glu	missense_variant	1/36	1		ENSP00000384093.1
CACNA1I	ENST00000401624.5	c.73C>G	p.Gln25Glu	missense_variant	1/36	1		ENSP00000383887.1
CACNA1I	ENST00000407673.5	c.73C>G	p.Gln25Glu	missense_variant	1/35	1		ENSP00000385680.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

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

Feb 26, 2024

The c.73C>G (p.Q25E) alteration is located in exon 1 (coding exon 1) of the CACNA1I gene. This alteration results from a C to G substitution at nucleotide position 73, causing the glutamine (Q) at amino acid position 25 to be replaced by a glutamic acid (E). 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	Benign	0.075
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Benign	0.58
DEOGEN2	Benign	0.0099	.;.;.;T
Eigen	Benign	0.026
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.52	T;T;T;T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.4	L;L;L;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.37	N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.31	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.57, 0.43	.;.;P;B
Vest4		0.37
MutPred		0.23		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.70
MPC		0.85
ClinPred		0.31	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.42

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-39966830;