NM_000719.7:c.5339G>A

Variant names:

• chr12-2679691-G-A
• rs756829999
• NM_000719.7:c.5339G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.5339G>A​(p.Arg1780His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1780C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.566
• Publications: 7 publications found

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]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2433615).
• BP6: Variant 12-2679691-G-A is Benign according to our data. Variant chr12-2679691-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 945968.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.5339G>A	p.Arg1780His	missense	Exon 42 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5339G>A	p.Arg1780His	missense	Exon 42 of 47	NP_001161095.1
	CACNA1C	NM_199460.4		c.5483G>A	p.Arg1828His	missense	Exon 44 of 50	NP_955630.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.5339G>A	p.Arg1780His	missense	Exon 42 of 47	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5339G>A	p.Arg1780His	missense	Exon 42 of 47	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.5573G>A	p.Arg1858His	missense	Exon 44 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000124 AC: 3 AN: 242558 AF XY: 0.0000152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000919

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459866 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6 AN XY: 726072

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.0000449 AC: 2 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26030

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39646

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85924

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111090

Other (OTH) AF: 0.0000498 AC: 3 AN: 60292

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74318

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	CACNA1C-related disorder (1)
-	1	-	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
CardioboostArm	Benign	0.000018
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	4.1
DANN	Benign	0.93
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.57
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.87	N
REVEL	Uncertain	0.53
Sift	Benign	0.21	T
Sift4G	Benign	0.080	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.37		Gain of catalytic residue at Y1832 (P = 0)
MVP		0.91
MPC		0.24
ClinPred		0.044	T
GERP RS		1.4
gMVP		0.29
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs756829999; hg19: chr12-2788857; COSMIC: COSV59697447; COSMIC: COSV59697447;