rs186741807

Variant names:

• chr12-2605669-C-T
• rs186741807
• NM_000719.7:c.3049-10C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.3049-10C>T variant causes a 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 intron
• Scores: Splicing: ADA: 0.00003263
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.425
• 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-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 166769.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 154 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3049-10C>T		intron_variant	Intron 23 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3049-10C>T		intron_variant	Intron 23 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3049-10C>T		intron_variant	Intron 23 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3049-10C>T		intron_variant	Intron 23 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3199-10C>T		intron_variant	Intron 24 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3049-10C>T		intron_variant	Intron 23 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3049-10C>T		intron_variant	Intron 23 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3214-10C>T		intron_variant	Intron 24 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3109-10C>T		intron_variant	Intron 24 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3049-10C>T		intron_variant	Intron 23 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3049-10C>T		intron_variant	Intron 23 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3049-10C>T		intron_variant	Intron 23 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3139-10C>T		intron_variant	Intron 23 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3139-10C>T		intron_variant	Intron 23 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3139-10C>T		intron_variant	Intron 23 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3139-10C>T		intron_variant	Intron 23 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3049-10C>T		intron_variant	Intron 23 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3124-10C>T		intron_variant	Intron 24 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3109-10C>T		intron_variant	Intron 24 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3049-10C>T		intron_variant	Intron 23 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3049-10C>T		intron_variant	Intron 23 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3049-10C>T		intron_variant	Intron 23 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3049-10C>T		intron_variant	Intron 23 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3124-10C>T		intron_variant	Intron 24 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3049-10C>T		intron_variant	Intron 23 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3049-10C>T		intron_variant	Intron 23 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3049-10C>T		intron_variant	Intron 23 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3049-10C>T		intron_variant	Intron 23 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3049-10C>T		intron_variant	Intron 23 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3049-10C>T		intron_variant	Intron 23 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3049-10C>T		intron_variant	Intron 23 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3049-10C>T		intron_variant	Intron 23 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3040-10C>T		intron_variant	Intron 23 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3049-10C>T		intron_variant	Intron 23 of 45			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1656-10C>T		intron_variant	Intron 21 of 26	5		ENSP00000437936.2

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

GnomAD2 exomes AF: 0.00118 AC: 297 AN: 251178 AF XY: 0.00125

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 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

African (AFR) AF: 0.000450 AC: 15 AN: 33322

American (AMR) AF: 0.00152 AC: 68 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00733 AC: 191 AN: 26074

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.00139 AC: 120 AN: 86084

European-Finnish (FIN) AF: 0.000450 AC: 24 AN: 53356

Middle Eastern (MID) AF: 0.0117 AC: 67 AN: 5750

European-Non Finnish (NFE) AF: 0.000417 AC: 461 AN: 1105250

Other (OTH) AF: 0.00161 AC: 97 AN: 60132

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

African (AFR) AF: 0.000168 AC: 7 AN: 41576

American (AMR) AF: 0.00170 AC: 26 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 68026

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00112 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

Oct 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: BS1 -

Jul 03, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CACNA1C-related disorder Benign:1

Jul 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Apr 09, 2019

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs186741807; hg19: chr12-2714835;