22-39570874-C-A

Variant names:

• chr22-39570874-C-A
• rs781264945
• NM_021096.4:c.122C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_021096.4(CACNA1I):​c.122C>A​(p.Pro41His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,642 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: CACNA1I NM_021096.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08
• Publications: 1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06654394).
• BS2: High AC in GnomAd4 at 8 AD gene.

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.122C>A	p.Pro41His	missense	Exon 1 of 37	NP_066919.2
	CACNA1I	NM_001003406.2		c.122C>A	p.Pro41His	missense	Exon 1 of 36	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.122C>A	p.Pro41His	missense	Exon 1 of 37	ENSP00000385019.3	Q9P0X4-1
	CACNA1I	ENST00000404898.5	TSL:1	c.122C>A	p.Pro41His	missense	Exon 1 of 36	ENSP00000384093.1	Q9P0X4-4
	CACNA1I	ENST00000401624.5	TSL:1	c.122C>A	p.Pro41His	missense	Exon 1 of 36	ENSP00000383887.1	Q9P0X4-2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000157 AC: 39 AN: 248990 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000118 AC: 173 AN: 1461486 Hom.: 1 Cov.: 32 AF XY: 0.000124 AC XY: 90 AN XY: 727054

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000626 AC: 28 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000124 AC: 138 AN: 1111794

Other (OTH) AF: 0.0000828 AC: 5 AN: 60364

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152156 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.000327 AC: 5 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000761 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.013
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.067	T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.4	L
PhyloP100		2.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.43
Sift	Benign	0.059	T
Sift4G	Uncertain	0.052	T
Polyphen		0.55	P
Vest4		0.29
MutPred		0.29		Gain of helix (P = 0.0117)
MVP		0.67
MPC		1.9
ClinPred		0.064	T
GERP RS		4.7
PromoterAI		-0.012	Neutral
Varity_R		0.10
gMVP		0.40
Mutation Taster		=100/0	polymorphism

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: rs781264945; hg19: chr22-39966879;