rs113595214

Variant names:

• chr12-2679449-C-T
• rs113595214
• NM_000719.7:c.5097C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.5097C>T​(p.Ala1699Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,556,730 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (60 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.137
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 12-2679449-C-T is Benign according to our data. Variant chr12-2679449-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.137 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00688 (1045/151934) while in subpopulation NFE AF = 0.0108 (731/67942). AF 95% confidence interval is 0.0101. There are 5 homozygotes in GnomAd4. There are 480 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1045 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.5097C>T	p.Ala1699Ala	synonymous	Exon 42 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5097C>T	p.Ala1699Ala	synonymous	Exon 42 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.5241C>T	p.Ala1747Ala	synonymous	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.5097C>T	p.Ala1699Ala	synonymous	Exon 42 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5097C>T	p.Ala1699Ala	synonymous	Exon 42 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.5331C>T	p.Ala1777Ala	synonymous	Exon 44 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.00688 AC: 1044 AN: 151812 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00518

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00699 AC: 1293 AN: 184942 AF XY: 0.00684

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00562

Gnomad ASJ exome AF: 0.00426

Gnomad EAS exome AF: 0.0000665

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.00947

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00810 AC: 11383 AN: 1404796 Hom.: 60 Cov.: 31 AF XY: 0.00801 AC XY: 5542 AN XY: 692098

African (AFR) AF: 0.00198 AC: 64 AN: 32322

American (AMR) AF: 0.00580 AC: 230 AN: 39634

Ashkenazi Jewish (ASJ) AF: 0.00303 AC: 70 AN: 23068

East Asian (EAS) AF: 0.0000526 AC: 2 AN: 38008

South Asian (SAS) AF: 0.00144 AC: 110 AN: 76278

European-Finnish (FIN) AF: 0.0147 AC: 732 AN: 49692

Middle Eastern (MID) AF: 0.0230 AC: 128 AN: 5562

European-Non Finnish (NFE) AF: 0.00884 AC: 9561 AN: 1082130

Other (OTH) AF: 0.00836 AC: 486 AN: 58102

GnomAD4 genome AF: 0.00688 AC: 1045 AN: 151934 Hom.: 5 Cov.: 33 AF XY: 0.00646 AC XY: 480 AN XY: 74256

African (AFR) AF: 0.00162 AC: 67 AN: 41484

American (AMR) AF: 0.00518 AC: 79 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4742

European-Finnish (FIN) AF: 0.0115 AC: 122 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0108 AC: 731 AN: 67942

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.00952 Hom.: 3

Bravo AF: 0.00588

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long QT syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		0.14
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113595214; hg19: chr12-2788615; COSMIC: COSV59760942; COSMIC: COSV59760942;