22-39598241-C-T

Variant names:

• chr22-39598241-C-T
• rs370960257
• NM_021096.4:c.327C>T

Variant summary

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

The NM_021096.4(CACNA1I):​c.327C>T​(p.Ser109Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,447,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S109S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CACNA1I NM_021096.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.86
• Publications: 0 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 (BayesDel_noAF=-0.65).
• BS2: High AC in GnomAdExome4 at 6 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.327C>T	p.Ser109Ser	synonymous	Exon 2 of 37	NP_066919.2
	CACNA1I	NM_001003406.2		c.327C>T	p.Ser109Ser	synonymous	Exon 2 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.327C>T	p.Ser109Ser	synonymous	Exon 2 of 37	ENSP00000385019.3	Q9P0X4-1
	CACNA1I	ENST00000404898.5	TSL:1	c.327C>T	p.Ser109Ser	synonymous	Exon 2 of 36	ENSP00000384093.1	Q9P0X4-4
	CACNA1I	ENST00000401624.5	TSL:1	c.327C>T	p.Ser109Ser	synonymous	Exon 2 of 36	ENSP00000383887.1	Q9P0X4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 228840 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1447672 Hom.: 0 Cov.: 32 AF XY: 0.00000556 AC XY: 4 AN XY: 719490

African (AFR) AF: 0.0000300 AC: 1 AN: 33288

American (AMR) AF: 0.0000229 AC: 1 AN: 43698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39262

South Asian (SAS) AF: 0.00 AC: 0 AN: 84488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1105890

Other (OTH) AF: 0.00 AC: 0 AN: 59938

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.025
DANN	Benign	0.94
PhyloP100		-7.9

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: rs370960257; hg19: chr22-39994246;