12-2605078-C-T

Variant names:

• chr12-2605078-C-T
• NM_000719.7:c.2961-3C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000719.7(CACNA1C):​c.2961-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 splice_region, intron
• Scores: Splicing: ADA: 0.9602
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.15).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3111-3C>T		splice_region_variant, intron_variant	Intron 23 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3126-3C>T		splice_region_variant, intron_variant	Intron 23 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3021-3C>T		splice_region_variant, intron_variant	Intron 23 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3051-3C>T		splice_region_variant, intron_variant	Intron 22 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3051-3C>T		splice_region_variant, intron_variant	Intron 22 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3051-3C>T		splice_region_variant, intron_variant	Intron 22 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3051-3C>T		splice_region_variant, intron_variant	Intron 22 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3036-3C>T		splice_region_variant, intron_variant	Intron 23 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3021-3C>T		splice_region_variant, intron_variant	Intron 23 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3036-3C>T		splice_region_variant, intron_variant	Intron 23 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2952-3C>T		splice_region_variant, intron_variant	Intron 22 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2961-3C>T		splice_region_variant, intron_variant	Intron 22 of 45			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1568-3C>T		splice_region_variant, intron_variant	Intron 20 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460358 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726564

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

May 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change falls in intron 22 of the CACNA1C gene. It does not directly change the encoded amino acid sequence of the CACNA1C protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 2091291). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Benign	16
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.29
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-2714244;