rs55792866

Variant names:

• chr12-2120310-G-A
• rs55792866
• NM_000719.7:c.372-15G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000719.7(CACNA1C):​c.372-15G>A variant causes a intron change. The variant allele was found at a frequency of 0.0251 in 1,264,380 control chromosomes in the GnomAD database, including 539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (88 hom., cov: 33)
  • Exomes 𝑓: 0.025 (451 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.47
• 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]

CACNA1C Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, 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: Orphanet, ClinGen
• 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: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-2120310-G-A is Benign according to our data. Variant chr12-2120310-G-A is described in ClinVar as Benign. ClinVar VariationId is 35768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0294 (4469/152234) while in subpopulation AFR AF = 0.0487 (2024/41538). AF 95% confidence interval is 0.047. There are 88 homozygotes in GnomAd4. There are 2154 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4469 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.372-15G>A		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.372-15G>A		intron	N/A	NP_001161095.1
	CACNA1C	NM_199460.4		c.372-15G>A		intron	N/A	NP_955630.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.372-15G>A		intron	N/A	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.372-15G>A		intron	N/A	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.462-15G>A		intron	N/A	ENSP00000507184.1

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 4461 AN: 152116 Hom.: 87 Cov.: 33

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0377

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0235

GnomAD2 exomes AF: 0.0234 AC: 5833 AN: 248948 AF XY: 0.0245

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.0000555

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.0245 AC: 27248 AN: 1112146 Hom.: 451 Cov.: 16 AF XY: 0.0254 AC XY: 14500 AN XY: 570822

African (AFR) AF: 0.0484 AC: 1293 AN: 26688

American (AMR) AF: 0.0118 AC: 521 AN: 44256

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 544 AN: 23996

East Asian (EAS) AF: 0.000184 AC: 7 AN: 38062

South Asian (SAS) AF: 0.0393 AC: 3112 AN: 79150

European-Finnish (FIN) AF: 0.0115 AC: 614 AN: 53290

Middle Eastern (MID) AF: 0.0313 AC: 160 AN: 5108

European-Non Finnish (NFE) AF: 0.0250 AC: 19844 AN: 792618

Other (OTH) AF: 0.0235 AC: 1153 AN: 48978

GnomAD4 genome AF: 0.0294 AC: 4469 AN: 152234 Hom.: 88 Cov.: 33 AF XY: 0.0289 AC XY: 2154 AN XY: 74438

African (AFR) AF: 0.0487 AC: 2024 AN: 41538

American (AMR) AF: 0.0156 AC: 239 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0375 AC: 181 AN: 4824

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10590

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0258 AC: 1755 AN: 68010

Other (OTH) AF: 0.0251 AC: 53 AN: 2110

Alfa AF: 0.0257 Hom.: 16

Bravo AF: 0.0294

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 11, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CACNA1C c.372-15G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.023 in 248948 control chromosomes in the gnomAD database, including 99 homozygotes. The observed variant frequency is approximately 2343-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.372-15G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Long QT syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long QT syndrome 8 Benign:1

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.67
PhyloP100		4.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs55792866; hg19: chr12-2229476;