22-39671635-G-A

Variant names:

• chr22-39671635-G-A
• rs5750870
• NM_021096.4:c.4540-564G>A

Variant summary

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

The NM_021096.4(CACNA1I):​c.4540-564G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 151,958 control chromosomes in the GnomAD database, including 21,782 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 0.52 (21782 hom., cov: 32)
• Consequence: CACNA1I NM_021096.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0810
• 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=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1I	NM_021096.4	c.4540-564G>A		intron_variant	Intron 26 of 36	ENST00000402142.4	NP_066919.2
CACNA1I	NM_001003406.2	c.4435-564G>A		intron_variant	Intron 25 of 35		NP_001003406.1
CACNA1I	XM_017029035.3	c.2686-564G>A		intron_variant	Intron 16 of 26		XP_016884524.1
CACNA1I	XM_017029036.2	c.2686-564G>A		intron_variant	Intron 16 of 26		XP_016884525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1I	ENST00000402142.4	c.4540-564G>A		intron_variant	Intron 26 of 36	1	NM_021096.4	ENSP00000385019.3
CACNA1I	ENST00000404898.5	c.4435-564G>A		intron_variant	Intron 25 of 35	1		ENSP00000384093.1
CACNA1I	ENST00000401624.5	c.4540-564G>A		intron_variant	Intron 26 of 35	1		ENSP00000383887.1
CACNA1I	ENST00000407673.5	c.4435-564G>A		intron_variant	Intron 25 of 34	1		ENSP00000385680.1

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79628 AN: 151838 Hom.: 21751 Cov.: 32

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.636

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.487

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

GnomAD4 genome AF: 0.525 AC: 79709 AN: 151958 Hom.: 21782 Cov.: 32 AF XY: 0.532 AC XY: 39512 AN XY: 74272

African (AFR) AF: 0.576 AC: 23850 AN: 41406

American (AMR) AF: 0.556 AC: 8486 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1502 AN: 3468

East Asian (EAS) AF: 0.958 AC: 4965 AN: 5182

South Asian (SAS) AF: 0.554 AC: 2661 AN: 4804

European-Finnish (FIN) AF: 0.517 AC: 5456 AN: 10544

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.457 AC: 31055 AN: 67958

Other (OTH) AF: 0.486 AC: 1028 AN: 2114

Alfa AF: 0.480 Hom.: 61385

Bravo AF: 0.530

Asia WGS AF: 0.713 AC: 2481 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.8
DANN	Benign	0.81
PhyloP100		0.081
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: rs5750870; hg19: chr22-40067640;