rs10848683

Positions:

• chr12-2681964-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The ENST00000327702.12(CACNA1C):​c.5459C>T​(p.Pro1820Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 1,596,264 control chromosomes in the GnomAD database, including 511,775 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1820P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.71 (40081 hom., cov: 32)
  • Exomes 𝑓: 0.80 (471694 hom.)
• Consequence: CACNA1C ENST00000327702.12 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.47

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:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2194 (greater than threshold 3.09). GenCC has associacion of gene with 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=1.8183505E-6).
• BP6: Variant 12-2681964-C-T is Benign according to our data. Variant chr12-2681964-C-T is described in ClinVar as [Benign]. Clinvar id is 136638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2681964-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5445-586C>T		intron_variant		ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5445-586C>T		intron_variant		ENST00000399603.6	NP_001161095.1
CACNA1C-AS1	NR_045725.1	n.334-4067G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5445-586C>T		intron_variant		5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.5445-586C>T		intron_variant		1	NM_000719.7	ENSP00000382563
CACNA1C-AS1	ENST00000501371.5	n.295-4067G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.713 AC: 107994 AN: 151514 Hom.: 40074 Cov.: 32

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.731

Gnomad ASJ AF: 0.821

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.842

Gnomad FIN AF: 0.854

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.817

Gnomad OTH AF: 0.711

GnomAD3 exomes AF: 0.777 AC: 193185 AN: 248494 Hom.: 76482 AF XY: 0.787 AC XY: 106275 AN XY: 135028

Gnomad AFR exome AF: 0.485

Gnomad AMR exome AF: 0.769

Gnomad ASJ exome AF: 0.815

Gnomad EAS exome AF: 0.591

Gnomad SAS exome AF: 0.845

Gnomad FIN exome AF: 0.852

Gnomad NFE exome AF: 0.813

Gnomad OTH exome AF: 0.789

GnomAD4 exome AF: 0.804 AC: 1162010 AN: 1444634 Hom.: 471694 Cov.: 30 AF XY: 0.807 AC XY: 580629 AN XY: 719614

Gnomad4 AFR exome AF: 0.473

Gnomad4 AMR exome AF: 0.764

Gnomad4 ASJ exome AF: 0.815

Gnomad4 EAS exome AF: 0.576

Gnomad4 SAS exome AF: 0.843

Gnomad4 FIN exome AF: 0.848

Gnomad4 NFE exome AF: 0.820

Gnomad4 OTH exome AF: 0.782

GnomAD4 genome AF: 0.712 AC: 108036 AN: 151630 Hom.: 40081 Cov.: 32 AF XY: 0.716 AC XY: 53006 AN XY: 74058

Gnomad4 AFR AF: 0.491

Gnomad4 AMR AF: 0.731

Gnomad4 ASJ AF: 0.821

Gnomad4 EAS AF: 0.593

Gnomad4 SAS AF: 0.842

Gnomad4 FIN AF: 0.854

Gnomad4 NFE AF: 0.817

Gnomad4 OTH AF: 0.712

Alfa AF: 0.796 Hom.: 81034

Bravo AF: 0.692

TwinsUK AF: 0.814 AC: 3018

ALSPAC AF: 0.807 AC: 3112

ESP6500AA AF: 0.504 AC: 1581

ESP6500EA AF: 0.821 AC: 5884

ExAC AF: 0.772 AC: 92945

Asia WGS AF: 0.708 AC: 2459 AN: 3478

EpiCase AF: 0.817

EpiControl AF: 0.807

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Timothy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.16
DANN	Benign	0.54
DEOGEN2	Benign	0.014	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00024	N
MetaRNN	Benign	0.0000018	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.19
Sift	Benign	0.24	T;T
Sift4G	Benign	0.10	T;T
Vest4		0.066
ClinPred		0.0050	T
GERP RS		1.6

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: rs10848683; hg19: chr12-2791130; COSMIC: COSV59713321; COSMIC: COSV59713321;