chr12-2686232-A-G

Position:

• chr12-2686232-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.5747A>G​(p.Gln1916Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000169 in 1,613,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.70

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 -12 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=0.014277607).
• BP6: Variant 12-2686232-A-G is Benign according to our data. Variant chr12-2686232-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263515.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000164 (25/152356) while in subpopulation EAS AF= 0.00463 (24/5188). AF 95% confidence interval is 0.00319. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5747A>G	p.Gln1916Arg	missense_variant	45/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5747A>G	p.Gln1916Arg	missense_variant	45/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5747A>G	p.Gln1916Arg	missense_variant	45/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5747A>G	p.Gln1916Arg	missense_variant	45/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6086A>G	p.Gln2029Arg	missense_variant	48/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5960A>G	p.Gln1987Arg	missense_variant	46/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5927A>G	p.Gln1976Arg	missense_variant	45/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5912A>G	p.Gln1971Arg	missense_variant	46/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5891A>G	p.Gln1964Arg	missense_variant	47/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5870A>G	p.Gln1957Arg	missense_variant	45/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5852A>G	p.Gln1951Arg	missense_variant	46/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5852A>G	p.Gln1951Arg	missense_variant	46/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5837A>G	p.Gln1946Arg	missense_variant	45/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5837A>G	p.Gln1946Arg	missense_variant	45/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5837A>G	p.Gln1946Arg	missense_variant	45/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5837A>G	p.Gln1946Arg	missense_variant	45/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5831A>G	p.Gln1944Arg	missense_variant	46/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5822A>G	p.Gln1941Arg	missense_variant	46/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5807A>G	p.Gln1936Arg	missense_variant	46/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5804A>G	p.Gln1935Arg	missense_variant	45/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5804A>G	p.Gln1935Arg	missense_variant	45/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5804A>G	p.Gln1935Arg	missense_variant	45/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5798A>G	p.Gln1933Arg	missense_variant	45/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5789A>G	p.Gln1930Arg	missense_variant	45/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5771A>G	p.Gln1924Arg	missense_variant	44/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5771A>G	p.Gln1924Arg	missense_variant	44/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5765A>G	p.Gln1922Arg	missense_variant	44/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5747A>G	p.Gln1916Arg	missense_variant	45/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5747A>G	p.Gln1916Arg	missense_variant	45/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5747A>G	p.Gln1916Arg	missense_variant	45/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5747A>G	p.Gln1916Arg	missense_variant	45/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5747A>G	p.Gln1916Arg	missense_variant	45/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5738A>G	p.Gln1913Arg	missense_variant	45/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5714A>G	p.Gln1905Arg	missense_variant	44/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000221 AC: 55 AN: 249300 Hom.: 0 AF XY: 0.000222 AC XY: 30 AN XY: 135246

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00295

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000169 AC: 247 AN: 1460958 Hom.: 0 Cov.: 32 AF XY: 0.000165 AC XY: 120 AN XY: 726800

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00599

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74514

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00463

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.000149 AC: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 25, 2019

Variant summary: The variant, CACNA1C c.5747A>G (p.Gln1916Arg) results in a conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 277978 control chromosomes, predominantly at a frequency of 0.0029 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 290 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.5747A>G has been reported in the literature in individuals affected with sudden cardiac death, sudden unexplained death syndrome and congenital long-QT syndrome (Liu_2017, Hata_2016, Chae_2017) including one large family study that showed incomplete penetrance for the variant. However, all these studies were of the same ethnic compoisition as seen in the control databases. Therefore, these reports do not provide unequivocal evidence supporting a deleterious outcome. Electrophysiological experiments using CACNA1C-Q1916R protein showed a reduction in amplitude of the current produced by the L-type calcium channel current. Moreover, in a human ventricular cell model used to stimulate action potential of endocardium and epicardium, the variant showed a 30% reduction in the conductance of the total ICa-L and AP duration at the level of 90% repolarization was reduced by 14.29% compared to WT (Liu_2017). A ClinVar submissions from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely benign, however, this was submitted prior to the Liu_2017 publication. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2017

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	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.014	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	-0.91	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.15
Sift	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;D;.
Sift4G	Benign	0.69	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.49, 0.55, 0.23, 0.082, 0.35, 0.60, 0.28, 0.30, 0.45, 0.73, 0.63	.;P;P;B;B;B;P;P;B;B;P;P;B;P;P;.;P;P;.;.;.;P;.
Vest4		0.73
MVP		0.71
MPC		0.32
ClinPred		0.070	T
GERP RS		4.8
gMVP		0.60

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: rs186867242; hg19: chr12-2795398; COSMIC: COSV59708445; COSMIC: COSV59708445;