22-39570825-C-G

Position:

• chr22-39570825-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000402142.4(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 ENST00000402142.4 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1I. . Gene score misZ 5.0511 (greater than the threshold 3.09). Trascript score misZ 3.2896 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, neurodevelopmental disorder with speech impairment and with or without seizures.
• 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	A2
CACNA1I	ENST00000404898.5	c.73C>G	p.Gln25Glu	missense_variant	1/36	1		ENSP00000384093	A2
CACNA1I	ENST00000401624.5	c.73C>G	p.Gln25Glu	missense_variant	1/36	1		ENSP00000383887	P4
CACNA1I	ENST00000407673.5	c.73C>G	p.Gln25Glu	missense_variant	1/35	1		ENSP00000385680	A2

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
MutationTaster	Benign	0.60	D;D;D;D;D;D
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;