rs367638447

Positions:

• chr12-2120412-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000719.7(CACNA1C):​c.459C>T​(p.Asn153Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000654 in 1,605,066 control chromosomes in the GnomAD database, including 1 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 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000064 (1 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.309

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 12-2120412-C-T is Benign according to our data. Variant chr12-2120412-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 264525.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.549C>T	p.Asn183Asn	synonymous_variant	3/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.459C>T	p.Asn153Asn	synonymous_variant	3/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.549C>T	p.Asn183Asn	synonymous_variant	3/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.459C>T	p.Asn153Asn	synonymous_variant	3/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.459C>T	p.Asn153Asn	synonymous_variant	3/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.459C>T	p.Asn153Asn	synonymous_variant	3/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.549C>T	p.Asn183Asn	synonymous_variant	3/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.549C>T	p.Asn183Asn	synonymous_variant	3/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.549C>T	p.Asn183Asn	synonymous_variant	3/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.549C>T	p.Asn183Asn	synonymous_variant	3/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.459C>T	p.Asn153Asn	synonymous_variant	3/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.459C>T	p.Asn153Asn	synonymous_variant	3/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.459C>T	p.Asn153Asn	synonymous_variant	3/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.459C>T	p.Asn153Asn	synonymous_variant	3/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.459C>T	p.Asn153Asn	synonymous_variant	3/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.459C>T	p.Asn153Asn	synonymous_variant	3/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.459C>T	p.Asn153Asn	synonymous_variant	3/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.459C>T	p.Asn153Asn	synonymous_variant	3/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.459C>T	p.Asn153Asn	synonymous_variant	3/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.459C>T	p.Asn153Asn	synonymous_variant	3/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.459C>T	p.Asn153Asn	synonymous_variant	3/46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.408C>T	p.Asn136Asn	synonymous_variant	2/6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.459C>T		non_coding_transcript_exon_variant	3/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000722 AC: 18 AN: 249322 Hom.: 0 AF XY: 0.0000887 AC XY: 12 AN XY: 135240

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000885

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000640 AC: 93 AN: 1452910 Hom.: 1 Cov.: 28 AF XY: 0.0000719 AC XY: 52 AN XY: 723440

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000697

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000688

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74332

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000869

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2022	Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CACNA1C-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2024

This variant is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 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	-0.40
CADD	Benign	4.2
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs367638447; hg19: chr12-2229578; COSMIC: COSV59750559;