12-2605744-G-C

Position:

• chr12-2605744-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.3114G>C​(p.Leu1038Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,614,058 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (15 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.65

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:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-2605744-G-C is Benign according to our data. Variant chr12-2605744-G-C is described in ClinVar as [Benign]. Clinvar id is 220348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2605744-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00562 (856/152304) while in subpopulation AFR AF= 0.0181 (754/41570). AF 95% confidence interval is 0.0171. There are 8 homozygotes in gnomad4. There are 424 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 856 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3264G>C	p.Leu1088Leu	synonymous_variant	25/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3279G>C	p.Leu1093Leu	synonymous_variant	25/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3174G>C	p.Leu1058Leu	synonymous_variant	25/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3204G>C	p.Leu1068Leu	synonymous_variant	24/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3204G>C	p.Leu1068Leu	synonymous_variant	24/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3204G>C	p.Leu1068Leu	synonymous_variant	24/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3204G>C	p.Leu1068Leu	synonymous_variant	24/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3189G>C	p.Leu1063Leu	synonymous_variant	25/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3174G>C	p.Leu1058Leu	synonymous_variant	25/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3189G>C	p.Leu1063Leu	synonymous_variant	25/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3105G>C	p.Leu1035Leu	synonymous_variant	24/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3114G>C	p.Leu1038Leu	synonymous_variant	24/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1721G>C		non_coding_transcript_exon_variant	22/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1721G>C		3_prime_UTR_variant	22/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 852 AN: 152186 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00151 AC: 380 AN: 251464 Hom.: 3 AF XY: 0.00116 AC XY: 157 AN XY: 135906

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000638 AC: 932 AN: 1461754 Hom.: 15 Cov.: 30 AF XY: 0.000593 AC XY: 431 AN XY: 727186

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000980

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00562 AC: 856 AN: 152304 Hom.: 8 Cov.: 32 AF XY: 0.00569 AC XY: 424 AN XY: 74466

Gnomad4 AFR AF: 0.0181

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00611

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 04, 2019

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2016

This alteration is classified as 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	-0.46
CADD	Benign	10
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs114139824; hg19: chr12-2714910;