chr12-2679490-A-G

Variant names:

• chr12-2679490-A-G
• rs769297492
• NM_000719.7:c.5138A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000719.7(CACNA1C):​c.5138A>G​(p.Asp1713Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000181 in 1,605,186 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D1713E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 6.60
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 12-2679490-A-G is Benign according to our data. Variant chr12-2679490-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 449139.
• BS2: High AC in GnomAd4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.5138A>G	p.Asp1713Gly	missense	Exon 42 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5138A>G	p.Asp1713Gly	missense	Exon 42 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.5282A>G	p.Asp1761Gly	missense	Exon 44 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.5138A>G	p.Asp1713Gly	missense	Exon 42 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5138A>G	p.Asp1713Gly	missense	Exon 42 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.5372A>G	p.Asp1791Gly	missense	Exon 44 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152024 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

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: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000292 AC: 7 AN: 239324 AF XY: 0.0000231

Gnomad AFR exome AF: 0.000211

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1453046 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8 AN XY: 721676

African (AFR) AF: 0.000331 AC: 11 AN: 33202

American (AMR) AF: 0.000114 AC: 5 AN: 44014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25778

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 85452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106620

Other (OTH) AF: 0.0000167 AC: 1 AN: 60028

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74396

African (AFR) AF: 0.000265 AC: 11 AN: 41512

American (AMR) AF: 0.00 AC: 0 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
CardioboostArm	Benign	0.0067
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.67
Sift	Benign	0.12	T
Sift4G	Benign	0.13	T
Polyphen		0.79	P
Vest4		0.49
MVP		0.88
MPC		0.25
ClinPred		0.23	T
GERP RS		4.6
gMVP		0.43
Mutation Taster		=26/74	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: rs769297492; hg19: chr12-2788656;