22-39634704-C-G

Position:

• chr22-39634704-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000402142.4(CACNA1I):​c.720C>G​(p.Phe240Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1I ENST00000402142.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.75

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1I	NM_021096.4	c.720C>G	p.Phe240Leu	missense_variant	5/37	ENST00000402142.4	NP_066919.2
CACNA1I	NM_001003406.2	c.720C>G	p.Phe240Leu	missense_variant	5/36		NP_001003406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1I	ENST00000402142.4	c.720C>G	p.Phe240Leu	missense_variant	5/37	1	NM_021096.4	ENSP00000385019	A2
CACNA1I	ENST00000404898.5	c.720C>G	p.Phe240Leu	missense_variant	5/36	1		ENSP00000384093	A2
CACNA1I	ENST00000401624.5	c.720C>G	p.Phe240Leu	missense_variant	5/36	1		ENSP00000383887	P4
CACNA1I	ENST00000407673.5	c.720C>G	p.Phe240Leu	missense_variant	5/35	1		ENSP00000385680	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;.;.;D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.0	M;M;M;M
MutationTaster	Benign	0.95	D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.032	D;D;D;D
Polyphen		0.91	P;P;P;P
Vest4		0.55
MutPred		0.60		Gain of catalytic residue at F240 (P = 0.0207);Gain of catalytic residue at F240 (P = 0.0207);Gain of catalytic residue at F240 (P = 0.0207);Gain of catalytic residue at F240 (P = 0.0207);
MVP		0.88
MPC		2.0
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr22-40030709;