22-39630029-C-T

Variant names:

• chr22-39630029-C-T
• rs5750860
• NM_021096.4:c.581-4536C>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.581-4536C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 152,090 control chromosomes in the GnomAD database, including 2,552 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 0.17 (2552 hom., cov: 32)
• Consequence: CACNA1I NM_021096.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.346
• Publications: 7 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.256 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.581-4536C>T		intron	N/A	NP_066919.2
	CACNA1I	NM_001003406.2		c.581-4536C>T		intron	N/A	NP_001003406.1	Q9P0X4-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1I	ENST00000402142.4	TSL:1 MANE Select	c.581-4536C>T		intron	N/A	ENSP00000385019.3	Q9P0X4-1
	CACNA1I	ENST00000404898.5	TSL:1	c.581-4536C>T		intron	N/A	ENSP00000384093.1	Q9P0X4-4
	CACNA1I	ENST00000401624.5	TSL:1	c.581-4536C>T		intron	N/A	ENSP00000383887.1	Q9P0X4-2

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25124 AN: 151972 Hom.: 2556 Cov.: 32

Gnomad AFR AF: 0.0591

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.173

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

GnomAD4 genome AF: 0.165 AC: 25121 AN: 152090 Hom.: 2552 Cov.: 32 AF XY: 0.170 AC XY: 12608 AN XY: 74340

African (AFR) AF: 0.0591 AC: 2452 AN: 41514

American (AMR) AF: 0.121 AC: 1857 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 685 AN: 3472

East Asian (EAS) AF: 0.158 AC: 815 AN: 5152

South Asian (SAS) AF: 0.268 AC: 1290 AN: 4812

European-Finnish (FIN) AF: 0.255 AC: 2698 AN: 10586

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14740 AN: 67954

Other (OTH) AF: 0.171 AC: 361 AN: 2112

Alfa AF: 0.196 Hom.: 2646

Bravo AF: 0.145

Asia WGS AF: 0.204 AC: 706 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.7
DANN	Benign	0.66
PhyloP100		0.35
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: rs5750860; hg19: chr22-40026034; COSMIC: COSV107408542;