rs184684058

Variant names:

• chr12-2595976-G-A
• rs184684058
• NM_000719.7:c.2766G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.2766G>A​(p.Pro922Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,612,976 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00049 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -6.76
• 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]

CACNA1C Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• 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: Ambry Genetics, Genomics England PanelApp, 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-2595976-G-A is Benign according to our data. Variant chr12-2595976-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195467.
• BP7: Synonymous conserved (PhyloP=-6.76 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000493 (75/152170) while in subpopulation AFR AF = 0.00169 (70/41532). AF 95% confidence interval is 0.00137. There are 2 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 75 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.2766G>A	p.Pro922Pro	synonymous	Exon 20 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.2766G>A	p.Pro922Pro	synonymous	Exon 20 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.2766G>A	p.Pro922Pro	synonymous	Exon 20 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.2766G>A	p.Pro922Pro	synonymous	Exon 20 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.2766G>A	p.Pro922Pro	synonymous	Exon 20 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.2856G>A	p.Pro952Pro	synonymous	Exon 20 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152052 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000205 AC: 51 AN: 248640 AF XY: 0.000185

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1460806 Hom.: 0 Cov.: 31 AF XY: 0.000116 AC XY: 84 AN XY: 726680

African (AFR) AF: 0.00200 AC: 67 AN: 33454

American (AMR) AF: 0.000425 AC: 19 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53146

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000747 AC: 83 AN: 1111464

Other (OTH) AF: 0.000116 AC: 7 AN: 60350

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152170 Hom.: 2 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74420

African (AFR) AF: 0.00169 AC: 70 AN: 41532

American (AMR) AF: 0.000196 AC: 3 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67980

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

Alfa AF: 0.000334 Hom.: 0

Bravo AF: 0.000514

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.6
DANN	Benign	0.67
PhyloP100		-6.8
Mutation Taster		=78/22	polymorphism

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: rs184684058; hg19: chr12-2705142;