chr12-2677841-G-A

Position:

• chr12-2677841-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_000719.7(CACNA1C):​c.5065G>A​(p.Ala1689Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 7.01

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:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5065G>A	p.Ala1689Thr	missense_variant	41/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5065G>A	p.Ala1689Thr	missense_variant	41/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5065G>A	p.Ala1689Thr	missense_variant	41/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5065G>A	p.Ala1689Thr	missense_variant	41/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5299G>A	p.Ala1767Thr	missense_variant	43/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5065G>A	p.Ala1689Thr	missense_variant	41/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5032G>A	p.Ala1678Thr	missense_variant	40/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5230G>A	p.Ala1744Thr	missense_variant	42/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5209G>A	p.Ala1737Thr	missense_variant	43/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5188G>A	p.Ala1730Thr	missense_variant	41/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5065G>A	p.Ala1689Thr	missense_variant	41/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5065G>A	p.Ala1689Thr	missense_variant	41/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5155G>A	p.Ala1719Thr	missense_variant	41/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5155G>A	p.Ala1719Thr	missense_variant	41/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5155G>A	p.Ala1719Thr	missense_variant	41/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5155G>A	p.Ala1719Thr	missense_variant	41/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5149G>A	p.Ala1717Thr	missense_variant	42/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5140G>A	p.Ala1714Thr	missense_variant	42/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5125G>A	p.Ala1709Thr	missense_variant	42/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5122G>A	p.Ala1708Thr	missense_variant	41/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5122G>A	p.Ala1708Thr	missense_variant	41/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5122G>A	p.Ala1708Thr	missense_variant	41/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5116G>A	p.Ala1706Thr	missense_variant	41/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5107G>A	p.Ala1703Thr	missense_variant	41/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5089G>A	p.Ala1697Thr	missense_variant	40/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5089G>A	p.Ala1697Thr	missense_variant	40/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5083G>A	p.Ala1695Thr	missense_variant	40/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5065G>A	p.Ala1689Thr	missense_variant	41/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5065G>A	p.Ala1689Thr	missense_variant	41/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5065G>A	p.Ala1689Thr	missense_variant	41/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5065G>A	p.Ala1689Thr	missense_variant	41/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5065G>A	p.Ala1689Thr	missense_variant	41/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5056G>A	p.Ala1686Thr	missense_variant	41/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5032G>A	p.Ala1678Thr	missense_variant	40/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 249216 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135210

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461598 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727074

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

Gnomad4 AFR AF: 0.0000241

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2013	p.Ala1689Thr (GCT>ACT): c.5065 G>A in exon 41 of the CACNA1C gene (NM_000719.6). The Ala1689Thr variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala1689Thr results in a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Threonine residue at a position that is conserved across species. The Ala1689Thr variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, in silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. Furthermore, no mutations affecting nearby residues have been reported in association with LQTS, indicating this region of the protein may be tolerant of change.With the clinical and molecular information available at this time, we cannot definitively determine if Ala1689Thr is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	- -

CACNA1C-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

The CACNA1C c.5065G>A variant is predicted to result in the amino acid substitution p.Ala1689Thr. This variant has been reported in an individual with aborted sudden death. Functionals studies of this variant showed no major alterations of the channel function (Blancard M et al 2018. PubMed ID: 30279520). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Timothy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Apr 17, 2019

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1689 of the CACNA1C protein (p.Ala1689Thr). This variant is present in population databases (rs368700869, gnomAD 0.01%). This missense change has been observed in individual(s) with aborted sudden death (PMID: 30279520). ClinVar contains an entry for this variant (Variation ID: 190677). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1C protein function. Experimental studies have shown that this missense change does not substantially affect CACNA1C function (PMID: 30279520). 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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

This alteration is classified as likely 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	Uncertain	0.076	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.7	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.51
Sift	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.65	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.95, 0.76, 0.070, 0.94, 0.93, 0.99, 0.73, 0.98, 0.99, 0.98, 0.99, 1.0, 1.0	.;P;P;B;P;P;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D;.
Vest4		0.54
MVP		0.87
MPC		0.46
ClinPred		0.40	T
GERP RS		4.5
gMVP		0.55

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: rs368700869; hg19: chr12-2787007; COSMIC: COSV59732681; COSMIC: COSV59732681;