22-39615268-G-T

Variant names:

• chr22-39615268-G-T
• rs3788568
• NM_021096.4:c.483-4042G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021096.4(CACNA1I):​c.483-4042G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 152,052 control chromosomes in the GnomAD database, including 12,757 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (12757 hom., cov: 32)
• Consequence: CACNA1I NM_021096.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.54
• Publications: 8 publications found

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]

CACNA1I Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with speech impairment and with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021096.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1I	NM_021096.4	MANE Select	c.483-4042G>T		intron	N/A	NP_066919.2
	CACNA1I	NM_001003406.2		c.483-4042G>T		intron	N/A	NP_001003406.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1I	ENST00000402142.4	TSL:1 MANE Select	c.483-4042G>T		intron	N/A	ENSP00000385019.3
	CACNA1I	ENST00000404898.5	TSL:1	c.483-4042G>T		intron	N/A	ENSP00000384093.1
	CACNA1I	ENST00000401624.5	TSL:1	c.483-4042G>T		intron	N/A	ENSP00000383887.1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60380 AN: 151934 Hom.: 12739 Cov.: 32

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.846

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.419

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.405

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.397 AC: 60432 AN: 152052 Hom.: 12757 Cov.: 32 AF XY: 0.403 AC XY: 29958 AN XY: 74314

African (AFR) AF: 0.378 AC: 15698 AN: 41480

American (AMR) AF: 0.415 AC: 6352 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1424 AN: 3470

East Asian (EAS) AF: 0.846 AC: 4374 AN: 5168

South Asian (SAS) AF: 0.473 AC: 2273 AN: 4804

European-Finnish (FIN) AF: 0.419 AC: 4425 AN: 10552

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.360 AC: 24473 AN: 67974

Other (OTH) AF: 0.409 AC: 862 AN: 2108

Alfa AF: 0.374 Hom.: 33588

Bravo AF: 0.400

Asia WGS AF: 0.618 AC: 2147 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.084
DANN	Benign	0.71
PhyloP100		-4.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3788568; hg19: chr22-40011273;