NM_021096.4:c.580+4A>T

Variant names:

• chr22-39619411-A-T
• NM_021096.4:c.580+4A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021096.4(CACNA1I):​c.580+4A>T variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1I NM_021096.4 splice_region, intron
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 4: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, phyloP100way_vertebrate [when BayesDel_noAF, Cadd was below the threshold]

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1I	NM_021096.4	c.580+4A>T		splice_region_variant, intron_variant	Intron 4 of 36	ENST00000402142.4	NP_066919.2
CACNA1I	NM_001003406.2	c.580+4A>T		splice_region_variant, intron_variant	Intron 4 of 35		NP_001003406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1I	ENST00000402142.4	c.580+4A>T		splice_region_variant, intron_variant	Intron 4 of 36	1	NM_021096.4	ENSP00000385019.3
CACNA1I	ENST00000404898.5	c.580+4A>T		splice_region_variant, intron_variant	Intron 4 of 35	1		ENSP00000384093.1
CACNA1I	ENST00000401624.5	c.580+4A>T		splice_region_variant, intron_variant	Intron 4 of 35	1		ENSP00000383887.1
CACNA1I	ENST00000407673.5	c.580+4A>T		splice_region_variant, intron_variant	Intron 4 of 34	1		ENSP00000385680.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.86		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-40015416;