12-2688726-G-C

Position:

• chr12-2688726-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.6064G>C​(p.Ala2022Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,601,444 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (1 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.418

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 -6 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). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. GenCC has associacion of the 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.085822344).
• BP6: Variant 12-2688726-G-C is Benign according to our data. Variant chr12-2688726-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411732.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6064G>C	p.Ala2022Pro	missense_variant	46/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6064G>C	p.Ala2022Pro	missense_variant	46/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6064G>C	p.Ala2022Pro	missense_variant	46/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6064G>C	p.Ala2022Pro	missense_variant	46/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6403G>C	p.Ala2135Pro	missense_variant	49/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6277G>C	p.Ala2093Pro	missense_variant	47/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6244G>C	p.Ala2082Pro	missense_variant	46/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6229G>C	p.Ala2077Pro	missense_variant	47/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6208G>C	p.Ala2070Pro	missense_variant	48/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6187G>C	p.Ala2063Pro	missense_variant	46/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6169G>C	p.Ala2057Pro	missense_variant	47/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6169G>C	p.Ala2057Pro	missense_variant	47/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6154G>C	p.Ala2052Pro	missense_variant	46/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6154G>C	p.Ala2052Pro	missense_variant	46/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6154G>C	p.Ala2052Pro	missense_variant	46/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6154G>C	p.Ala2052Pro	missense_variant	46/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6148G>C	p.Ala2050Pro	missense_variant	47/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6139G>C	p.Ala2047Pro	missense_variant	47/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6124G>C	p.Ala2042Pro	missense_variant	47/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6121G>C	p.Ala2041Pro	missense_variant	46/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6121G>C	p.Ala2041Pro	missense_variant	46/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6121G>C	p.Ala2041Pro	missense_variant	46/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6115G>C	p.Ala2039Pro	missense_variant	46/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6106G>C	p.Ala2036Pro	missense_variant	46/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6088G>C	p.Ala2030Pro	missense_variant	45/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6088G>C	p.Ala2030Pro	missense_variant	45/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6082G>C	p.Ala2028Pro	missense_variant	45/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6064G>C	p.Ala2022Pro	missense_variant	46/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6064G>C	p.Ala2022Pro	missense_variant	46/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6064G>C	p.Ala2022Pro	missense_variant	46/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6064G>C	p.Ala2022Pro	missense_variant	46/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6064G>C	p.Ala2022Pro	missense_variant	46/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6055G>C	p.Ala2019Pro	missense_variant	46/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6031G>C	p.Ala2011Pro	missense_variant	45/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000174 AC: 4 AN: 230536 Hom.: 0 AF XY: 0.0000158 AC XY: 2 AN XY: 126336

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000339

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000292

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1449246 Hom.: 1 Cov.: 33 AF XY: 0.0000111 AC XY: 8 AN XY: 719612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000702

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000633

Gnomad4 OTH exome AF: 0.0000669

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2023

The p.A2022P variant (also known as c.6064G>C), located in coding exon 46 of the CACNA1C gene, results from a G to C substitution at nucleotide position 6064. The alanine at codon 2022 is replaced by proline, an amino acid with highly similar properties. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a cardiac disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, the association of this alteration with CACNA1C-related neurodevelopmental disorder is unknown; however, the association of this alteration with long QT syndrome or Timothy syndrome is unlikely. -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.012	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.35	N
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.086	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	-1.1	T
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.091
Sift	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.0010, 0.0020, 0.0080, 0.0030	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.21
MVP		0.28
MPC		0.25
ClinPred		0.070	T
GERP RS		4.3
gMVP		0.47

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: rs758974396; hg19: chr12-2797892;