chr22-39570851-C-T

Variant names:

• chr22-39570851-C-T
• rs3747178
• NM_021096.4:c.99C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_021096.4(CACNA1I):​c.99C>T​(p.Ser33Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,613,156 control chromosomes in the GnomAD database, including 83,656 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.27 (6807 hom., cov: 31)
  • Exomes 𝑓: 0.31 (76849 hom.)
• Consequence: CACNA1I NM_021096.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.92
• Publications: 17 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-39570851-C-T is Benign according to our data. Variant chr22-39570851-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060116.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-2.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.706 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.99C>T	p.Ser33Ser	synonymous	Exon 1 of 37	NP_066919.2
	CACNA1I	NM_001003406.2		c.99C>T	p.Ser33Ser	synonymous	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.99C>T	p.Ser33Ser	synonymous	Exon 1 of 37	ENSP00000385019.3	Q9P0X4-1
	CACNA1I	ENST00000404898.5	TSL:1	c.99C>T	p.Ser33Ser	synonymous	Exon 1 of 36	ENSP00000384093.1	Q9P0X4-4
	CACNA1I	ENST00000401624.5	TSL:1	c.99C>T	p.Ser33Ser	synonymous	Exon 1 of 36	ENSP00000383887.1	Q9P0X4-2

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40350 AN: 151876 Hom.: 6799 Cov.: 31

Gnomad AFR AF: 0.0920

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.724

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.306

GnomAD2 exomes AF: 0.324 AC: 80196 AN: 247356 AF XY: 0.323

Gnomad AFR exome AF: 0.0849

Gnomad AMR exome AF: 0.284

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.724

Gnomad FIN exome AF: 0.388

Gnomad NFE exome AF: 0.309

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.312 AC: 456224 AN: 1461162 Hom.: 76849 Cov.: 36 AF XY: 0.311 AC XY: 226156 AN XY: 726892

African (AFR) AF: 0.0876 AC: 2933 AN: 33476

American (AMR) AF: 0.290 AC: 12951 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 8033 AN: 26130

East Asian (EAS) AF: 0.744 AC: 29540 AN: 39696

South Asian (SAS) AF: 0.266 AC: 22967 AN: 86252

European-Finnish (FIN) AF: 0.387 AC: 20580 AN: 53120

Middle Eastern (MID) AF: 0.311 AC: 1794 AN: 5766

European-Non Finnish (NFE) AF: 0.304 AC: 338049 AN: 1111650

Other (OTH) AF: 0.321 AC: 19377 AN: 60362

GnomAD4 genome AF: 0.266 AC: 40356 AN: 151994 Hom.: 6807 Cov.: 31 AF XY: 0.272 AC XY: 20219 AN XY: 74250

African (AFR) AF: 0.0918 AC: 3810 AN: 41494

American (AMR) AF: 0.292 AC: 4456 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1053 AN: 3466

East Asian (EAS) AF: 0.725 AC: 3739 AN: 5158

South Asian (SAS) AF: 0.292 AC: 1403 AN: 4812

European-Finnish (FIN) AF: 0.378 AC: 3985 AN: 10550

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.308 AC: 20908 AN: 67936

Other (OTH) AF: 0.311 AC: 657 AN: 2110

Alfa AF: 0.281 Hom.: 3071

Bravo AF: 0.257

Asia WGS AF: 0.436 AC: 1510 AN: 3478

EpiCase AF: 0.309

EpiControl AF: 0.301

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CACNA1I-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.84
DANN	Benign	0.55
PhyloP100		-2.9
PromoterAI		-0.0056	Neutral
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: rs3747178; hg19: chr22-39966856; COSMIC: COSV60821862;