rs1060503445

Variant names:

• chr12-2584563-TCAC-T
• rs1060503445
• NM_000719.7:c.2286_2288delCAC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_000719.7(CACNA1C):​c.2286_2288delCAC​(p.Thr763del) variant causes a disruptive inframe deletion 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_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.30

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000719.7. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2376_2378delCAC	p.Thr793del	disruptive_inframe_deletion	Exon 16 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2451_2453delCAC	p.Thr818del	disruptive_inframe_deletion	Exon 17 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2376_2378delCAC	p.Thr793del	disruptive_inframe_deletion	Exon 16 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2376_2378delCAC	p.Thr793del	disruptive_inframe_deletion	Exon 16 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2376_2378delCAC	p.Thr793del	disruptive_inframe_deletion	Exon 16 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2376_2378delCAC	p.Thr793del	disruptive_inframe_deletion	Exon 16 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2361_2363delCAC	p.Thr788del	disruptive_inframe_deletion	Exon 17 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2361_2363delCAC	p.Thr788del	disruptive_inframe_deletion	Exon 17 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2277_2279delCAC	p.Thr760del	disruptive_inframe_deletion	Exon 16 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2286_2288delCAC	p.Thr763del	disruptive_inframe_deletion	Exon 16 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*893_*895delCAC		non_coding_transcript_exon_variant	Exon 14 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*893_*895delCAC		3_prime_UTR_variant	Exon 14 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Jan 05, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel in-frame deletion with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CACNA1C-related disease. This sequence change deletes 3 nucleotides from exon 16 of the CACNA1C mRNA (c.2286_2288delCAC). This leads to the deletion of 1 amino acid residue in the CACNA1C protein (p.Thr763del) but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060503445; hg19: chr12-2693729;