12-2668886-A-C

Variant names:

• chr12-2668886-A-C
• rs114898435
• NM_000719.7:c.4624-47A>C

Variant summary

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

The NM_000719.7(CACNA1C):​c.4624-47A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,147,284 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 1 publications found

Genes affected

CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

CACNA1C-AS2 (HGNC:40118): (CACNA1C antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. 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
	CACNA1C	NM_000719.7	MANE Select	c.4624-47A>C		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.4624-47A>C		intron	N/A	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.4768-47A>C		intron	N/A	NP_955630.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.4624-47A>C		intron	N/A	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.4624-47A>C		intron	N/A	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.4858-47A>C		intron	N/A	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000174 AC: 20 AN: 1147284 Hom.: 0 Cov.: 16 AF XY: 0.0000137 AC XY: 8 AN XY: 585826

African (AFR) AF: 0.00 AC: 0 AN: 27284

American (AMR) AF: 0.00 AC: 0 AN: 44312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24208

East Asian (EAS) AF: 0.00 AC: 0 AN: 38156

South Asian (SAS) AF: 0.00 AC: 0 AN: 79886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5138

European-Non Finnish (NFE) AF: 0.0000242 AC: 20 AN: 825066

Other (OTH) AF: 0.00 AC: 0 AN: 50128

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.67
DANN	Benign	0.67
PhyloP100		-1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs114898435; hg19: chr12-2778052;