12-2567722-C-A

Variant names:

• chr12-2567722-C-A
• rs757507674
• NM_000719.7:c.1823C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_000719.7(CACNA1C):​c.1823C>A​(p.Thr608Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.74

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 6 ACMG points.

• PM1: In a topological_domain Extracellular (size 8) in uniprot entity CAC1C_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1913C>A	p.Thr638Asn	missense_variant	Exon 13 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1988C>A	p.Thr663Asn	missense_variant	Exon 14 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1913C>A	p.Thr638Asn	missense_variant	Exon 13 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1913C>A	p.Thr638Asn	missense_variant	Exon 13 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1913C>A	p.Thr638Asn	missense_variant	Exon 13 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1913C>A	p.Thr638Asn	missense_variant	Exon 13 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1898C>A	p.Thr633Asn	missense_variant	Exon 14 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1898C>A	p.Thr633Asn	missense_variant	Exon 14 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1814C>A	p.Thr605Asn	missense_variant	Exon 13 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1823C>A	p.Thr608Asn	missense_variant	Exon 13 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*430C>A		non_coding_transcript_exon_variant	Exon 11 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*430C>A		3_prime_UTR_variant	Exon 11 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249064 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135062

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461492 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727034

Gnomad4 AFR exome AF: 0.0000597

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.79	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	1.1	D
MutationAssessor	Benign	0.94	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.13	T;T;D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.099	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.99, 0.91, 0.98, 0.79, 0.95, 1.0, 1.0, 1.0	.;D;D;P;D;P;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.74
MutPred		0.60		.;Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);Gain of catalytic residue at L605 (P = 2e-04);
MVP		0.89
MPC		2.0
ClinPred		0.63	D
GERP RS		5.3
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: rs757507674; hg19: chr12-2676888;