chr12-2682561-G-T

Position:

• chr12-2682561-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000719.7(CACNA1C):​c.5456G>T​(p.Arg1819Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1819Q) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.18

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]

CACNA1C-AS1 (HGNC:):

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• 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). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. GenCC has associacion of the 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25465715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5456G>T	p.Arg1819Leu	missense_variant	43/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5456G>T	p.Arg1819Leu	missense_variant	43/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5456G>T	p.Arg1819Leu	missense_variant	43/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5456G>T	p.Arg1819Leu	missense_variant	43/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5795G>T	p.Arg1932Leu	missense_variant	46/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5669G>T	p.Arg1890Leu	missense_variant	44/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5636G>T	p.Arg1879Leu	missense_variant	43/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5621G>T	p.Arg1874Leu	missense_variant	44/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5600G>T	p.Arg1867Leu	missense_variant	45/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5579G>T	p.Arg1860Leu	missense_variant	43/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5561G>T	p.Arg1854Leu	missense_variant	44/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5561G>T	p.Arg1854Leu	missense_variant	44/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5546G>T	p.Arg1849Leu	missense_variant	43/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5546G>T	p.Arg1849Leu	missense_variant	43/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5546G>T	p.Arg1849Leu	missense_variant	43/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5546G>T	p.Arg1849Leu	missense_variant	43/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5540G>T	p.Arg1847Leu	missense_variant	44/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5531G>T	p.Arg1844Leu	missense_variant	44/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5516G>T	p.Arg1839Leu	missense_variant	44/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5513G>T	p.Arg1838Leu	missense_variant	43/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5513G>T	p.Arg1838Leu	missense_variant	43/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5513G>T	p.Arg1838Leu	missense_variant	43/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5507G>T	p.Arg1836Leu	missense_variant	43/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5498G>T	p.Arg1833Leu	missense_variant	43/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5480G>T	p.Arg1827Leu	missense_variant	42/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5480G>T	p.Arg1827Leu	missense_variant	42/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5474G>T	p.Arg1825Leu	missense_variant	42/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5456G>T	p.Arg1819Leu	missense_variant	43/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5456G>T	p.Arg1819Leu	missense_variant	43/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5456G>T	p.Arg1819Leu	missense_variant	43/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5456G>T	p.Arg1819Leu	missense_variant	43/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5456G>T	p.Arg1819Leu	missense_variant	43/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5447G>T	p.Arg1816Leu	missense_variant	43/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5423G>T	p.Arg1808Leu	missense_variant	42/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74270

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.44
Sift	Benign	0.039	D;T;D;D;T;T;D;D;D;D;D;D;D;T;D;T;D;D;D;T;T;T;.
Sift4G	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.057, 0.0010, 0.12, 0.012, 0.15, 0.0030, 0.0060, 0.0, 0.034, 0.0090, 0.010, 0.25, 0.064, 0.017, 0.28	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.46
MVP		0.77
MPC		0.26
ClinPred		0.64	D
GERP RS		3.9
gMVP		0.46

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: rs764212214; hg19: chr12-2791727; COSMIC: COSV100222074; COSMIC: COSV100222074;