chr12-2688442-C-T

Variant names:

• chr12-2688442-C-T
• rs750451768
• NM_000719.7:c.5785-5C>T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000719.7(CACNA1C):​c.5785-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CACNA1C NM_000719.7 splice_region, intron
• Scores: Splicing: ADA: 0.0002164
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0960

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-AS1 (HGNC:):

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 12-2688442-C-T is Benign according to our data. Variant chr12-2688442-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 456984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5785-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5785-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5785-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5785-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6124-5C>T		splice_region_variant, intron_variant	Intron 48 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5998-5C>T		splice_region_variant, intron_variant	Intron 46 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5965-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5950-5C>T		splice_region_variant, intron_variant	Intron 46 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5929-5C>T		splice_region_variant, intron_variant	Intron 47 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5908-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5890-5C>T		splice_region_variant, intron_variant	Intron 46 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5890-5C>T		splice_region_variant, intron_variant	Intron 46 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5875-5C>T		splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5875-5C>T		splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5875-5C>T		splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5875-5C>T		splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5869-5C>T		splice_region_variant, intron_variant	Intron 46 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5860-5C>T		splice_region_variant, intron_variant	Intron 46 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5845-5C>T		splice_region_variant, intron_variant	Intron 46 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5842-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5842-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5842-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5836-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5827-5C>T		splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5809-5C>T		splice_region_variant, intron_variant	Intron 44 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5809-5C>T		splice_region_variant, intron_variant	Intron 44 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5803-5C>T		splice_region_variant, intron_variant	Intron 44 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5785-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5785-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5785-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5785-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5785-5C>T		splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5776-5C>T		splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5752-5C>T		splice_region_variant, intron_variant	Intron 44 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000325 AC: 8 AN: 246240 Hom.: 0 AF XY: 0.0000299 AC XY: 4 AN XY: 133988

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461354 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727002

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CACNA1C-related disorder Benign:1

Feb 10, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Long QT syndrome Benign:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jan 27, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	10
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.064
SpliceAI score (max)		0.070		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: rs750451768; hg19: chr12-2797608; COSMIC: COSV100223946; COSMIC: COSV100223946;