rs200935321

Variant names:

• chr12-2493304-C-A
• NM_000719.7:c.1031C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2493304-C-A
• chr12-2493304-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000719.7(CACNA1C):​c.1031C>A​(p.Thr344Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,792 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: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 5 ACMG points.

• 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, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1121C>A	p.Thr374Asn	missense_variant	Exon 7 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1121C>A	p.Thr374Asn	missense_variant	Exon 7 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1121C>A	p.Thr374Asn	missense_variant	Exon 7 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1121C>A	p.Thr374Asn	missense_variant	Exon 7 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1121C>A	p.Thr374Asn	missense_variant	Exon 7 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1121C>A	p.Thr374Asn	missense_variant	Exon 7 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1022C>A	p.Thr341Asn	missense_variant	Exon 7 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.968C>A	p.Thr323Asn	missense_variant	Exon 6 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.1031C>A		non_coding_transcript_exon_variant	Exon 7 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.94	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	Uncertain	2.7	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.5	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	0.91
Sift	Uncertain	0.016	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	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 1.0, 1.0	.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.97
MutPred		0.61		Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);
MVP		0.95
MPC		2.4
ClinPred		0.99	D
GERP RS		5.1
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-2602470;