12-2581611-C-G

Variant names:

• chr12-2581611-C-G
• rs1057524804
• NM_000719.7:c.1917C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000719.7(CACNA1C):​c.1917C>G​(p.Asn639Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.24

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a repeat II (size 246) in uniprot entity CAC1C_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000719.7
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2007C>G	p.Asn669Lys	missense_variant	Exon 14 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2082C>G	p.Asn694Lys	missense_variant	Exon 15 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2007C>G	p.Asn669Lys	missense_variant	Exon 14 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2007C>G	p.Asn669Lys	missense_variant	Exon 14 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2007C>G	p.Asn669Lys	missense_variant	Exon 14 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2007C>G	p.Asn669Lys	missense_variant	Exon 14 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1992C>G	p.Asn664Lys	missense_variant	Exon 15 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1992C>G	p.Asn664Lys	missense_variant	Exon 15 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1908C>G	p.Asn636Lys	missense_variant	Exon 14 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1917C>G	p.Asn639Lys	missense_variant	Exon 14 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*524C>G		non_coding_transcript_exon_variant	Exon 12 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*524C>G		3_prime_UTR_variant	Exon 12 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Timothy syndrome Uncertain:1

Apr 13, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 24, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The N639K variant has not been published as pathogenic or been reported as benign to our knowledge. It was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N639K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nonetheless, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, all of which would further clarify pathogenicity. -

Long QT syndrome Uncertain:1

Apr 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 expected to disrupt CACNA1C protein function. This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 393134). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 639 of the CACNA1C protein (p.Asn639Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.42, 0.88, 1.0, 0.85, 0.89, 0.14, 0.85, 0.99, 0.25, 0.16, 0.28	.;B;P;D;P;P;B;B;P;D;B;B;P;B;B;P;.;P;B;.;.;.;B
Vest4		0.83
MutPred		0.64		.;Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);Gain of catalytic residue at N639 (P = 0.0151);
MVP		0.92
MPC		2.3
ClinPred		0.99	D
GERP RS		4.3
gMVP		0.96

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: rs1057524804; hg19: chr12-2690777;