rs112414325

Variant names:

• chr12-2688580-G-A
• rs112414325
• NM_000719.7:c.5918G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000719.7(CACNA1C):​c.5918G>A​(p.Arg1973Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,954 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1973W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (36 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:16
• Conservation: PhyloP100: 2.58
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006121576).
• BP6: Variant 12-2688580-G-A is Benign according to our data. Variant chr12-2688580-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00195 (297/152296) while in subpopulation SAS AF = 0.018 (87/4826). AF 95% confidence interval is 0.015. There are 3 homozygotes in GnomAd4. There are 170 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 297 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.5918G>A	p.Arg1973Gln	missense	Exon 46 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5918G>A	p.Arg1973Gln	missense	Exon 46 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.6167G>A	p.Arg2056Gln	missense	Exon 49 of 50	NP_955630.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.5918G>A	p.Arg1973Gln	missense	Exon 46 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5918G>A	p.Arg1973Gln	missense	Exon 46 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.6257G>A	p.Arg2086Gln	missense	Exon 49 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 296 AN: 152178 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00345 AC: 857 AN: 248420 AF XY: 0.00425

Gnomad AFR exome AF: 0.0000649

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.00414

GnomAD4 exome AF: 0.00234 AC: 3418 AN: 1461658 Hom.: 36 Cov.: 33 AF XY: 0.00276 AC XY: 2004 AN XY: 727118

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00141 AC: 63 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 332 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0156 AC: 1345 AN: 86252

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53354

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5768

European-Non Finnish (NFE) AF: 0.00126 AC: 1403 AN: 1111870

Other (OTH) AF: 0.00363 AC: 219 AN: 60374

GnomAD4 genome AF: 0.00195 AC: 297 AN: 152296 Hom.: 3 Cov.: 33 AF XY: 0.00228 AC XY: 170 AN XY: 74468

African (AFR) AF: 0.000409 AC: 17 AN: 41562

American (AMR) AF: 0.00176 AC: 27 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.0180 AC: 87 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 68018

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00212 Hom.: 4

Bravo AF: 0.00153

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000518 AC: 2

ESP6500EA AF: 0.00218 AC: 18

ExAC AF: 0.00357 AC: 431

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not provided (9)
-	1	3	not specified (4)
-	-	1	CACNA1C-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	Short QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Benign	0.83
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.94	T
PhyloP100		2.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.18
Sift	Benign	0.48	T
Sift4G	Benign	0.59	T
Polyphen		0.032	B
Vest4		0.32
MVP		0.77
MPC		0.22
ClinPred		0.013	T
GERP RS		5.0
gMVP		0.43
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs112414325; hg19: chr12-2797746; COSMIC: COSV59694963; COSMIC: COSV59694963;