12-2685827-C-T

Variant names:

• chr12-2685827-C-T
• rs185788586
• NM_000719.7:c.5665C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000719.7(CACNA1C):​c.5665C>T​(p.Arg1889Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,612,066 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. R1889L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (125 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.66
• Publications: 12 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=0.0021506548).
• BP6: Variant 12-2685827-C-T is Benign according to our data. Variant chr12-2685827-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

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.5665C>T	p.Arg1889Cys	missense	Exon 44 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5665C>T	p.Arg1889Cys	missense	Exon 44 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.5914C>T	p.Arg1972Cys	missense	Exon 47 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.5665C>T	p.Arg1889Cys	missense	Exon 44 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5665C>T	p.Arg1889Cys	missense	Exon 44 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.6004C>T	p.Arg2002Cys	missense	Exon 47 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 561 AN: 152194 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0318

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: 0.000588

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.0102 AC: 2537 AN: 248796 AF XY: 0.00770

Gnomad AFR exome AF: 0.000582

Gnomad AMR exome AF: 0.0697

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000684

Gnomad OTH exome AF: 0.00646

GnomAD4 exome AF: 0.00260 AC: 3789 AN: 1459754 Hom.: 125 Cov.: 31 AF XY: 0.00227 AC XY: 1649 AN XY: 726274

African (AFR) AF: 0.000568 AC: 19 AN: 33456

American (AMR) AF: 0.0655 AC: 2927 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86200

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53398

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.000624 AC: 693 AN: 1110124

Other (OTH) AF: 0.00204 AC: 123 AN: 60302

GnomAD4 genome AF: 0.00368 AC: 561 AN: 152312 Hom.: 11 Cov.: 32 AF XY: 0.00395 AC XY: 294 AN XY: 74478

African (AFR) AF: 0.000746 AC: 31 AN: 41564

American (AMR) AF: 0.0318 AC: 486 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00170 Hom.: 2

Bravo AF: 0.00694

ESP6500AA AF: 0.00126 AC: 5

ESP6500EA AF: 0.00144 AC: 12

ExAC AF: 0.00743 AC: 898

EpiCase AF: 0.00104

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	Timothy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0094	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.64	D
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.86	T
PhyloP100		2.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.046	D
Sift4G	Benign	0.14	T
Polyphen		0.0010	B
Vest4		0.28
MPC		0.26
ClinPred		0.011	T
GERP RS		4.3
gMVP		0.44
Mutation Taster		=100/0	polymorphism (auto)

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: rs185788586; hg19: chr12-2794993;