rs201258230

Positions:

• chr12-2611965-C-A
• chr12-2611965-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.3780C>A​(p.Gly1260Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,613,512 control chromosomes in the GnomAD database, including 10 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 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (10 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.130

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 12-2611965-C-A is Benign according to our data. Variant chr12-2611965-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93403.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=4}. Variant chr12-2611965-C-A is described in Lovd as [Benign]. Variant chr12-2611965-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00132 (201/152250) while in subpopulation AMR AF= 0.00333 (51/15296). AF 95% confidence interval is 0.00261. There are 0 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 201 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3930C>A	p.Gly1310Gly	synonymous_variant	30/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3945C>A	p.Gly1315Gly	synonymous_variant	30/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3840C>A	p.Gly1280Gly	synonymous_variant	30/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3870C>A	p.Gly1290Gly	synonymous_variant	29/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3870C>A	p.Gly1290Gly	synonymous_variant	29/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3870C>A	p.Gly1290Gly	synonymous_variant	29/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3870C>A	p.Gly1290Gly	synonymous_variant	29/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3855C>A	p.Gly1285Gly	synonymous_variant	30/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3840C>A	p.Gly1280Gly	synonymous_variant	30/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3855C>A	p.Gly1285Gly	synonymous_variant	30/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3771C>A	p.Gly1257Gly	synonymous_variant	29/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3780C>A	p.Gly1260Gly	synonymous_variant	29/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*2387C>A		non_coding_transcript_exon_variant	27/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*2387C>A		3_prime_UTR_variant	27/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152132 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00213 AC: 534 AN: 250230 Hom.: 7 AF XY: 0.00234 AC XY: 318 AN XY: 135630

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.00454

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00411

GnomAD4 exome AF: 0.00164 AC: 2397 AN: 1461262 Hom.: 10 Cov.: 29 AF XY: 0.00170 AC XY: 1237 AN XY: 727012

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00446

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00147

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152250 Hom.: 0 Cov.: 31 AF XY: 0.00124 AC XY: 92 AN XY: 74446

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00188 Hom.: 1

Bravo AF: 0.00193

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 31, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CACNA1C: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2022	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 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). -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2015

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	8.8
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs201258230; hg19: chr12-2721131;