22-39598223-C-G

Position:

• chr22-39598223-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The ENST00000402142.4(CACNA1I):​c.309C>G​(p.Asp103Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,455,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CACNA1I ENST00000402142.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.344

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 Likely_benign. Variant got -5 ACMG points.

• 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=0.09268695).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1I	NM_021096.4	c.309C>G	p.Asp103Glu	missense_variant	2/37	ENST00000402142.4	NP_066919.2
CACNA1I	NM_001003406.2	c.309C>G	p.Asp103Glu	missense_variant	2/36		NP_001003406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1I	ENST00000402142.4	c.309C>G	p.Asp103Glu	missense_variant	2/37	1	NM_021096.4	ENSP00000385019	A2
CACNA1I	ENST00000404898.5	c.309C>G	p.Asp103Glu	missense_variant	2/36	1		ENSP00000384093	A2
CACNA1I	ENST00000401624.5	c.309C>G	p.Asp103Glu	missense_variant	2/36	1		ENSP00000383887	P4
CACNA1I	ENST00000407673.5	c.309C>G	p.Asp103Glu	missense_variant	2/35	1		ENSP00000385680	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000836 AC: 2 AN: 239264 Hom.: 0 AF XY: 0.00000770 AC XY: 1 AN XY: 129836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000593

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1455452 Hom.: 0 Cov.: 32 AF XY: 0.00000553 AC XY: 4 AN XY: 723572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000679

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: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000340

ExAC AF: 0.00000826 AC: 1

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 11, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 103 of the CACNA1I protein (p.Asp103Glu). This variant is present in population databases (rs771894093, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CACNA1I-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	8.0
DANN	Benign	0.82
DEOGEN2	Benign	0.19	.;.;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.093	T;T;T;T
MetaSVM	Uncertain	-0.043	T
MutationAssessor	Benign	-1.1	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	1.4	N;N;N;N
REVEL	Benign	0.25
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.093
MutPred		0.39		Loss of stability (P = 0.2216);Loss of stability (P = 0.2216);Loss of stability (P = 0.2216);Loss of stability (P = 0.2216);
MVP		0.64
MPC		0.70
ClinPred		0.021	T
GERP RS		-6.8
Varity_R		0.053
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs771894093; hg19: chr22-39994228;