rs136855

Variant names:

• chr22-39665678-A-G
• rs136855
• NM_021096.4:c.3978+54A>G

Variant summary

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

The NM_021096.4(CACNA1I):​c.3978+54A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,594,494 control chromosomes in the GnomAD database, including 43,491 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 0.26 (5619 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37872 hom.)
• Consequence: CACNA1I NM_021096.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08
• 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1I	NM_021096.4	c.3978+54A>G		intron_variant	Intron 22 of 36	ENST00000402142.4	NP_066919.2
CACNA1I	NM_001003406.2	c.3873+54A>G		intron_variant	Intron 21 of 35		NP_001003406.1
CACNA1I	XM_017029035.3	c.2124+54A>G		intron_variant	Intron 12 of 26		XP_016884524.1
CACNA1I	XM_017029036.2	c.2124+54A>G		intron_variant	Intron 12 of 26		XP_016884525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1I	ENST00000402142.4	c.3978+54A>G		intron_variant	Intron 22 of 36	1	NM_021096.4	ENSP00000385019.3
CACNA1I	ENST00000404898.5	c.3873+54A>G		intron_variant	Intron 21 of 35	1		ENSP00000384093.1
CACNA1I	ENST00000401624.5	c.3978+54A>G		intron_variant	Intron 22 of 35	1		ENSP00000383887.1
CACNA1I	ENST00000407673.5	c.3873+54A>G		intron_variant	Intron 21 of 34	1		ENSP00000385680.1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39457 AN: 151858 Hom.: 5617 Cov.: 32

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.0401

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.286

GnomAD4 exome AF: 0.222 AC: 320848 AN: 1442518 Hom.: 37872 Cov.: 30 AF XY: 0.220 AC XY: 157487 AN XY: 714954

African (AFR) AF: 0.365 AC: 12106 AN: 33124

American (AMR) AF: 0.290 AC: 12732 AN: 43912

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7349 AN: 25386

East Asian (EAS) AF: 0.0437 AC: 1721 AN: 39360

South Asian (SAS) AF: 0.128 AC: 10831 AN: 84880

European-Finnish (FIN) AF: 0.232 AC: 12111 AN: 52170

Middle Eastern (MID) AF: 0.303 AC: 1727 AN: 5692

European-Non Finnish (NFE) AF: 0.226 AC: 248445 AN: 1098506

Other (OTH) AF: 0.232 AC: 13826 AN: 59488

GnomAD4 genome AF: 0.260 AC: 39492 AN: 151976 Hom.: 5619 Cov.: 32 AF XY: 0.253 AC XY: 18784 AN XY: 74264

African (AFR) AF: 0.359 AC: 14875 AN: 41390

American (AMR) AF: 0.249 AC: 3799 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1000 AN: 3464

East Asian (EAS) AF: 0.0402 AC: 208 AN: 5176

South Asian (SAS) AF: 0.113 AC: 543 AN: 4812

European-Finnish (FIN) AF: 0.220 AC: 2330 AN: 10588

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15864 AN: 67956

Other (OTH) AF: 0.286 AC: 603 AN: 2108

Alfa AF: 0.246 Hom.: 16341

Bravo AF: 0.272

Asia WGS AF: 0.140 AC: 487 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.73
PhyloP100		-2.1
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: rs136855; hg19: chr22-40061683; COSMIC: COSV60803532;