rs542914369

Variant names:

• chr12-2685833-G-C
• rs542914369
• NM_000719.7:c.5671G>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_000719.7(CACNA1C):​c.5671G>C​(p.Ala1891Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,609,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.64

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07022217).
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6010G>C	p.Ala2004Pro	missense_variant	Exon 47 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5884G>C	p.Ala1962Pro	missense_variant	Exon 45 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5851G>C	p.Ala1951Pro	missense_variant	Exon 44 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5836G>C	p.Ala1946Pro	missense_variant	Exon 45 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5815G>C	p.Ala1939Pro	missense_variant	Exon 46 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5794G>C	p.Ala1932Pro	missense_variant	Exon 44 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5776G>C	p.Ala1926Pro	missense_variant	Exon 45 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5776G>C	p.Ala1926Pro	missense_variant	Exon 45 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5761G>C	p.Ala1921Pro	missense_variant	Exon 44 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5761G>C	p.Ala1921Pro	missense_variant	Exon 44 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5761G>C	p.Ala1921Pro	missense_variant	Exon 44 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5761G>C	p.Ala1921Pro	missense_variant	Exon 44 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5755G>C	p.Ala1919Pro	missense_variant	Exon 45 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5746G>C	p.Ala1916Pro	missense_variant	Exon 45 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5731G>C	p.Ala1911Pro	missense_variant	Exon 45 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5728G>C	p.Ala1910Pro	missense_variant	Exon 44 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5728G>C	p.Ala1910Pro	missense_variant	Exon 44 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5728G>C	p.Ala1910Pro	missense_variant	Exon 44 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5722G>C	p.Ala1908Pro	missense_variant	Exon 44 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5713G>C	p.Ala1905Pro	missense_variant	Exon 44 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5695G>C	p.Ala1899Pro	missense_variant	Exon 43 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5695G>C	p.Ala1899Pro	missense_variant	Exon 43 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5689G>C	p.Ala1897Pro	missense_variant	Exon 43 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5671G>C	p.Ala1891Pro	missense_variant	Exon 44 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5662G>C	p.Ala1888Pro	missense_variant	Exon 44 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5638G>C	p.Ala1880Pro	missense_variant	Exon 43 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 248772 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134970

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000960 AC: 14 AN: 1457630 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 725362

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000332

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74498

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 07, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The A1891P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although this variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations, the 1000 Genomes Project reports A1891P was observed in approximately 0.1% of alleles from individuals of African background. The A1891P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating this region of the gene is not known to harbor pathogenic variants. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -

Long QT syndrome Uncertain:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1891 of the CACNA1C protein (p.Ala1891Pro). This variant is present in population databases (rs542914369, gnomAD 0.03%). 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: 279723). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. 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. -

Cardiovascular phenotype Benign:1

Nov 10, 2024

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_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.79
DEOGEN2	Benign	0.0022	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.61	D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.070	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.45	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.18
Sift	Benign	0.42	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.73, 0.0010, 0.0, 0.78, 0.81, 0.0060, 0.57, 0.70, 0.88, 0.95, 0.51	.;P;B;B;B;P;P;P;B;P;P;P;P;P;P;.;P;P;.;.;.;P;.
Vest4		0.34
MVP		0.63
MPC		0.29
ClinPred		0.017	T
GERP RS		2.3
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs542914369; hg19: chr12-2794999;