rs186741807

Positions:

• chr12-2605669-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.3049-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000746 in 1,606,636 control chromosomes in the GnomAD database, including 3 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 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (3 hom.)
• Consequence: CACNA1C NM_000719.7 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003263
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.425

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-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-2605669-C-T is Benign according to our data. Variant chr12-2605669-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166769.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=5}. Variant chr12-2605669-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00101 (154/152326) while in subpopulation SAS AF= 0.00228 (11/4830). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 154 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.3049-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000399655.6
CACNA1C	NM_001167623.2	c.3049-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3049-10C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.3049-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000719.7
CACNA1C-AS3	ENST00000543559.1	n.20+1752G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00118 AC: 297 AN: 251178 Hom.: 1 AF XY: 0.00125 AC XY: 170 AN XY: 135794

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00814

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000827

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.000718 AC: 1044 AN: 1454310 Hom.: 3 Cov.: 29 AF XY: 0.000768 AC XY: 556 AN XY: 723994

Gnomad4 AFR exome AF: 0.000450

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00733

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00139

Gnomad4 FIN exome AF: 0.000450

Gnomad4 NFE exome AF: 0.000417

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74488

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00112

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2017	Variant summary: c.3049-10>T in CACNA1C gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.001174 (142/120926 chrs tested), including 1 homozygote. The observed frequency exceeds the maximum expected allele frequency for a pathogenic variant of 0.00001, suggesting that it is a common polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but is cited as Likely Benign/Benign by reputable databases/clinical laboratory. Taking together the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	CACNA1C: BS1 -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

CACNA1C-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congestive heart failure Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Apr 09, 2019

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs186741807; hg19: chr12-2714835;