22-39576157-T-C

Variant names:

• chr22-39576157-T-C
• rs3788556
• NM_021096.4:c.236+5169T>C

Variant summary

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

The NM_021096.4(CACNA1I):​c.236+5169T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 152,062 control chromosomes in the GnomAD database, including 28,443 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 0.60 (28443 hom., cov: 33)
• Consequence: CACNA1I NM_021096.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0150
• Publications: 10 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.941 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1I	NM_021096.4	MANE Select	c.236+5169T>C		intron	N/A	NP_066919.2
	CACNA1I	NM_001003406.2		c.236+5169T>C		intron	N/A	NP_001003406.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1I	ENST00000402142.4	TSL:1 MANE Select	c.236+5169T>C		intron	N/A	ENSP00000385019.3
	CACNA1I	ENST00000404898.5	TSL:1	c.236+5169T>C		intron	N/A	ENSP00000384093.1
	CACNA1I	ENST00000401624.5	TSL:1	c.236+5169T>C		intron	N/A	ENSP00000383887.1

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91258 AN: 151944 Hom.: 28407 Cov.: 33

Gnomad AFR AF: 0.716

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.963

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.613

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

GnomAD4 genome AF: 0.601 AC: 91346 AN: 152062 Hom.: 28443 Cov.: 33 AF XY: 0.605 AC XY: 44996 AN XY: 74326

African (AFR) AF: 0.716 AC: 29712 AN: 41474

American (AMR) AF: 0.590 AC: 9013 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1974 AN: 3468

East Asian (EAS) AF: 0.963 AC: 4981 AN: 5172

South Asian (SAS) AF: 0.514 AC: 2483 AN: 4830

European-Finnish (FIN) AF: 0.618 AC: 6530 AN: 10560

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34724 AN: 67970

Other (OTH) AF: 0.617 AC: 1303 AN: 2112

Alfa AF: 0.548 Hom.: 51836

Bravo AF: 0.610

Asia WGS AF: 0.757 AC: 2631 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	5.3
DANN	Benign	0.78
PhyloP100		-0.015
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: rs3788556; hg19: chr22-39972162;