rs34534613

Variant names:

• chr12-2115283-G-A
• rs34534613
• NM_000719.7:c.109G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000719.7(CACNA1C):​c.109G>A​(p.Gly37Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,592,144 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0040 (23 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 9.76
• Publications: 15 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]

CACNA1C Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• long QT syndrome 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
• Brugada syndrome 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.011658281).
• BP6: Variant 12-2115283-G-A is Benign according to our data. Variant chr12-2115283-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00329 (501/152364) while in subpopulation NFE AF = 0.00465 (316/68028). AF 95% confidence interval is 0.00422. There are 1 homozygotes in GnomAd4. There are 241 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 501 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.109G>A	p.Gly37Arg	missense	Exon 2 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.109G>A	p.Gly37Arg	missense	Exon 2 of 47	NP_001161095.1
	CACNA1C	NM_199460.4		c.109G>A	p.Gly37Arg	missense	Exon 2 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.109G>A	p.Gly37Arg	missense	Exon 2 of 47	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.109G>A	p.Gly37Arg	missense	Exon 2 of 47	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.199G>A	p.Gly67Arg	missense	Exon 2 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 501 AN: 152246 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00464

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00346 AC: 728 AN: 210138 AF XY: 0.00349

Gnomad AFR exome AF: 0.000336

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00151

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00776

Gnomad NFE exome AF: 0.00531

Gnomad OTH exome AF: 0.00284

GnomAD4 exome AF: 0.00403 AC: 5809 AN: 1439780 Hom.: 23 Cov.: 32 AF XY: 0.00399 AC XY: 2851 AN XY: 714318

African (AFR) AF: 0.000516 AC: 17 AN: 32936

American (AMR) AF: 0.00215 AC: 91 AN: 42364

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 32 AN: 25708

East Asian (EAS) AF: 0.00 AC: 0 AN: 38418

South Asian (SAS) AF: 0.000384 AC: 32 AN: 83388

European-Finnish (FIN) AF: 0.00952 AC: 472 AN: 49590

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5742

European-Non Finnish (NFE) AF: 0.00452 AC: 4977 AN: 1102120

Other (OTH) AF: 0.00296 AC: 176 AN: 59514

GnomAD4 genome AF: 0.00329 AC: 501 AN: 152364 Hom.: 1 Cov.: 34 AF XY: 0.00323 AC XY: 241 AN XY: 74516

African (AFR) AF: 0.000914 AC: 38 AN: 41596

American (AMR) AF: 0.00196 AC: 30 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00941 AC: 100 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00465 AC: 316 AN: 68028

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00408 Hom.: 11

Bravo AF: 0.00251

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000517 AC: 2

ESP6500EA AF: 0.00318 AC: 26

ExAC AF: 0.00335 AC: 403

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	CACNA1C-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	Timothy 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
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.058	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
MetaRNN	Benign	0.012	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.4	L
PhyloP100		9.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.36		Loss of loop (P = 0.0073)
MVP		0.98
MPC		2.0
ClinPred		0.035	T
GERP RS		5.8
PromoterAI		0.017	Neutral
gMVP		0.76
Mutation Taster		=36/64	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: rs34534613; hg19: chr12-2224449;