chr12-2679516-T-G

Variant names:

• chr12-2679516-T-G
• rs751493277
• NM_000719.7:c.5164T>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.5164T>G​(p.Phe1722Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,611,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.46
• Publications: 0 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 12-2679516-T-G is Benign according to our data. Variant chr12-2679516-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526947.
• BS2: High AC in GnomAdExome4 at 6 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.5164T>G	p.Phe1722Val	missense	Exon 42 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5164T>G	p.Phe1722Val	missense	Exon 42 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.5308T>G	p.Phe1770Val	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.5164T>G	p.Phe1722Val	missense	Exon 42 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5164T>G	p.Phe1722Val	missense	Exon 42 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.5398T>G	p.Phe1800Val	missense	Exon 44 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152086 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: 0.000386

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: 0.0000285 AC: 7 AN: 245250 AF XY: 0.0000375

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459678 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 725918

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110732

Other (OTH) AF: 0.0000166 AC: 1 AN: 60310

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152086 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000826 AC: 1

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
CardioboostArm	Benign	0.00016
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.2	L
PhyloP100		5.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.62
Sift	Benign	0.33	T
Sift4G	Benign	0.51	T
Polyphen		1.0	D
Vest4		0.73
MutPred		0.31		Gain of catalytic residue at F1766 (P = 0.0679)
MVP		0.96
MPC		0.26
ClinPred		0.15	T
GERP RS		4.6
gMVP		0.72
Mutation Taster		=39/61	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: rs751493277; hg19: chr12-2788682;