12-2605109-T-TTGCGAGTCC

Variant names:

• chr12-2605109-T-TTGCGAGTCC
• NM_000719.7:c.2997_3005dupCCTGCGAGT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4 PP3

The NM_000719.7(CACNA1C):​c.2997_3005dupCCTGCGAGT​(p.Val1002_Leu1003insLeuArgVal) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• Publications: 0 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]

CACNA1C-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000719.7.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.2997_3005dupCCTGCGAGT	p.Val1002_Leu1003insLeuArgVal	disruptive_inframe_insertion	Exon 23 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.2997_3005dupCCTGCGAGT	p.Val1002_Leu1003insLeuArgVal	disruptive_inframe_insertion	Exon 23 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.3057_3065dupCCTGCGAGT	p.Val1022_Leu1023insLeuArgVal	disruptive_inframe_insertion	Exon 24 of 50	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.2997_3005dupCCTGCGAGT	p.Val1002_Leu1003insLeuArgVal	disruptive_inframe_insertion	Exon 23 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.2997_3005dupCCTGCGAGT	p.Val1002_Leu1003insLeuArgVal	disruptive_inframe_insertion	Exon 23 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.3147_3155dupCCTGCGAGT	p.Val1052_Leu1053insLeuArgVal	disruptive_inframe_insertion	Exon 24 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0

Splicing

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

Other links and lift over

hg19: chr12-2714275;