rs578233776

Variant names:

• chr12-2685810-C-T
• rs578233776
• NM_000719.7:c.5648C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.5648C>T​(p.Pro1883Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1883P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.39

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-AS1 (HGNC:):

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2295965).
• BP6: Variant 12-2685810-C-T is Benign according to our data. Variant chr12-2685810-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 581391.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5648C>T	p.Pro1883Leu	missense_variant	Exon 44 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5648C>T	p.Pro1883Leu	missense_variant	Exon 44 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5648C>T	p.Pro1883Leu	missense_variant	Exon 44 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5648C>T	p.Pro1883Leu	missense_variant	Exon 44 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5987C>T	p.Pro1996Leu	missense_variant	Exon 47 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5861C>T	p.Pro1954Leu	missense_variant	Exon 45 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5828C>T	p.Pro1943Leu	missense_variant	Exon 44 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5813C>T	p.Pro1938Leu	missense_variant	Exon 45 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5792C>T	p.Pro1931Leu	missense_variant	Exon 46 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5771C>T	p.Pro1924Leu	missense_variant	Exon 44 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5753C>T	p.Pro1918Leu	missense_variant	Exon 45 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5753C>T	p.Pro1918Leu	missense_variant	Exon 45 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5738C>T	p.Pro1913Leu	missense_variant	Exon 44 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5738C>T	p.Pro1913Leu	missense_variant	Exon 44 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5738C>T	p.Pro1913Leu	missense_variant	Exon 44 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5738C>T	p.Pro1913Leu	missense_variant	Exon 44 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5732C>T	p.Pro1911Leu	missense_variant	Exon 45 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5723C>T	p.Pro1908Leu	missense_variant	Exon 45 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5708C>T	p.Pro1903Leu	missense_variant	Exon 45 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5705C>T	p.Pro1902Leu	missense_variant	Exon 44 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5705C>T	p.Pro1902Leu	missense_variant	Exon 44 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5705C>T	p.Pro1902Leu	missense_variant	Exon 44 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5699C>T	p.Pro1900Leu	missense_variant	Exon 44 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5690C>T	p.Pro1897Leu	missense_variant	Exon 44 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5672C>T	p.Pro1891Leu	missense_variant	Exon 43 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5672C>T	p.Pro1891Leu	missense_variant	Exon 43 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5666C>T	p.Pro1889Leu	missense_variant	Exon 43 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5648C>T	p.Pro1883Leu	missense_variant	Exon 44 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5648C>T	p.Pro1883Leu	missense_variant	Exon 44 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5648C>T	p.Pro1883Leu	missense_variant	Exon 44 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5648C>T	p.Pro1883Leu	missense_variant	Exon 44 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5648C>T	p.Pro1883Leu	missense_variant	Exon 44 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5639C>T	p.Pro1880Leu	missense_variant	Exon 44 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5615C>T	p.Pro1872Leu	missense_variant	Exon 43 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 248910 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135046

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461292 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726948

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74472

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:1

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1883 of the CACNA1C protein (p.Pro1883Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with atrial septal defects (PMID: 32368696). This variant is also known as P1966L. ClinVar contains an entry for this variant (Variation ID: 581391). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Benign:1

Sep 22, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.0052
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.7	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.026	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.13, 0.036, 0.21, 0.12, 0.72, 0.85, 0.56, 0.0030, 0.67, 0.75, 0.91, 0.15, 0.52, 0.70, 0.38, 0.47	.;B;B;B;B;P;P;P;B;P;P;P;B;P;P;.;P;B;.;.;.;P;.
Vest4		0.54
MVP		0.44
MPC		0.20
ClinPred		0.67	D
GERP RS		4.3
gMVP		0.62

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: rs578233776; hg19: chr12-2794976; COSMIC: COSV105226661; COSMIC: COSV105226661;