12-2691054-A-G

Position:

• chr12-2691054-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.6272A>G​(p.Asn2091Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00076 in 1,607,328 control chromosomes in the GnomAD database, including 2 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 0.00075 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (2 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 3.21

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 -12 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 7.2674 (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=0.054399014).
• BP6: Variant 12-2691054-A-G is Benign according to our data. Variant chr12-2691054-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216482.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=4}. Variant chr12-2691054-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000749 (114/152250) while in subpopulation NFE AF= 0.000897 (61/67996). AF 95% confidence interval is 0.000716. There are 0 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6272A>G	p.Asn2091Ser	missense_variant	47/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6272A>G	p.Asn2091Ser	missense_variant	47/47	ENST00000399603.6	NP_001161095.1
CACNA1C-AS1	NR_045725.1	n.89+15T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6272A>G	p.Asn2091Ser	missense_variant	47/47	5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.6272A>G	p.Asn2091Ser	missense_variant	47/47	1	NM_000719.7	ENSP00000382563
CACNA1C-AS1	ENST00000501371.5	n.50+15T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000486 AC: 113 AN: 232392 Hom.: 0 AF XY: 0.000449 AC XY: 57 AN XY: 126932

Gnomad AFR exome AF: 0.000600

Gnomad AMR exome AF: 0.000211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000650

Gnomad SAS exome AF: 0.000414

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000663

Gnomad OTH exome AF: 0.00105

GnomAD4 exome AF: 0.000761 AC: 1107 AN: 1455078 Hom.: 2 Cov.: 30 AF XY: 0.000769 AC XY: 556 AN XY: 723254

Gnomad4 AFR exome AF: 0.000690

Gnomad4 AMR exome AF: 0.000228

Gnomad4 ASJ exome AF: 0.0000771

Gnomad4 EAS exome AF: 0.000330

Gnomad4 SAS exome AF: 0.000530

Gnomad4 FIN exome AF: 0.0000380

Gnomad4 NFE exome AF: 0.000847

Gnomad4 OTH exome AF: 0.00112

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000725 AC XY: 54 AN XY: 74446

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000713 Hom.: 0

Bravo AF: 0.000672

ESP6500AA AF: 0.000527 AC: 2

ESP6500EA AF: 0.000611 AC: 5

ExAC AF: 0.000539 AC: 65

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 09, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2024	Published functional studies suggest a gain of function effect (PMID: 27218670); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25633834, 24690944, 27218670, 34426522, 30172029, 31737537, 30027834, 24440382) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 15, 2021	The CACNA1C c.6272A>G; p.Asn2091Ser variant (rs201090446) is reported in the literature in an individual with sudden unexpected death and a history of syncope (Sutphin 2016). This variant is found in the general population with an overall allele frequency of 0.05% (129/263770 alleles) in the Genome Aggregation Database. The asparagine at codon 2091 is moderately conserved, and computational analyses predict that this variant is neutral (REVEL: 0.139). However, functional studies of the variant protein indicate altered electrophysiological properties, including increased current density compared to wildtype protein (Sutphin 2016). Due to limited information, the clinical significance of the p.Asn2091Ser variant is uncertain at this time. References: Sutphin et al. Molecular and Functional Characterization of Rare CACNA1C Variants in Sudden Unexplained Death in the Young. Congenit Heart Dis. 2016 Dec;11(6):683-692. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CACNA1C: BP4, BS1, BS2 -

Timothy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Apr 06, 2017

- -

Cardiac arrhythmia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Aug 18, 2016

- -

CACNA1C-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2021

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 26, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2020

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	-0.44	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.054	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	-0.67	T
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Benign	0.14
Sift	Uncertain	0.023	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99, 0.65, 0.82, 0.090, 1.0, 1.0, 0.036, 0.97, 0.99, 0.40	.;D;P;P;B;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;B;.
Vest4		0.32
MVP		0.59
MPC		0.21
ClinPred		0.033	T
GERP RS		4.5
gMVP		0.57

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: rs201090446; hg19: chr12-2800220;