12-2512975-C-T

Variant names:

• chr12-2512975-C-T
• NM_000719.7:c.1381C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_000719.7(CACNA1C):​c.1381C>T​(p.Pro461Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P461H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

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 topological_domain Cytoplasmic (size 122) in uniprot entity CAC1C_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-2512976-C-A is described in Lovd as [Likely_pathogenic].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1471C>T	p.Pro491Ser	missense_variant	Exon 9 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1471C>T	p.Pro491Ser	missense_variant	Exon 9 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1471C>T	p.Pro491Ser	missense_variant	Exon 9 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1471C>T	p.Pro491Ser	missense_variant	Exon 9 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1471C>T	p.Pro491Ser	missense_variant	Exon 9 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1471C>T	p.Pro491Ser	missense_variant	Exon 9 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1372C>T	p.Pro458Ser	missense_variant	Exon 9 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1381C>T	p.Pro461Ser	missense_variant	Exon 9 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.1113+19589C>T		intron_variant	Intron 7 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long qt syndrome 8 Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.1381C>T (p.Pro461Ser) in CACNA1C gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Proline at position 461 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. The residue is conserved across species. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.4	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.5	N;D;D;N;D;N;D;D;D;N;D;N;D;D;D;N;D;N;D;D;N;D;D
REVEL	Uncertain	0.53
Sift	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.22	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, 0.054, 0.73, 0.43, 1.0, 0.56, 1.0	.;D;.;B;P;B;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.69
MutPred		0.24		Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);Gain of phosphorylation at P461 (P = 0.007);
MVP		0.87
MPC		1.6
ClinPred		0.95	D
GERP RS		4.4
gMVP		0.93

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: chr12-2622141;