12-2581611-C-A

Position:

• chr12-2581611-C-A

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>A​(p.Asn639Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,417,586 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• 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 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1917C>A	p.Asn639Lys	missense_variant	14/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1917C>A	p.Asn639Lys	missense_variant	14/47	ENST00000399603.6	NP_001161095.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1417586 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 700684

Gnomad4 AFR exome AF: 0.00

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: 9.19e-7

Gnomad4 OTH exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 02, 2018

- -

Congenital long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 02, 2020

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to lysine (exon 14). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). Note: this region has <30x coverage. (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. Moderate amino acid change, very high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. Located in the intracellular region between subunits S4 and S5 of Domain II (PMID: 31004778). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. PMID: 31004778; p.(Asn639Thr) considered likely pathogenic in a female proband, her brother and mother with prolonged QT/?Timothy syndrome. Functional studies of CRISPR/Cas9-edited hiPSC-CMs had indicated an impact on the channel (increased action potential and slower voltage-dependent inactivation). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. ClinVar: VUS x1 (condition: Timothy syndrome) with an alternative nucleotide change (C>G) causing the same amino acid change also reported as a VUS x2 in ClinVar (conditions: Timothy syndrome, Not provided). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 30, 2020

This sequence change replaces asparagine with lysine at codon 639 of the CACNA1C protein (p.Asn639Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 560694). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

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;