12-2610661-G-C

Position:

• chr12-2610661-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000719.7(CACNA1C):​c.3679G>C​(p.Val1227Leu) 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 1,461,886 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.

• 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: 1.55

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 57) in uniprot entity CAC1C_HUMAN there are 4 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 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3877402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3679G>C	p.Val1227Leu	missense_variant	28/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3679G>C	p.Val1227Leu	missense_variant	28/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3679G>C	p.Val1227Leu	missense_variant	28/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3679G>C	p.Val1227Leu	missense_variant	28/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3829G>C	p.Val1277Leu	missense_variant	29/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3679G>C	p.Val1227Leu	missense_variant	28/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3679G>C	p.Val1227Leu	missense_variant	28/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3844G>C	p.Val1282Leu	missense_variant	29/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3739G>C	p.Val1247Leu	missense_variant	29/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3679G>C	p.Val1227Leu	missense_variant	28/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3679G>C	p.Val1227Leu	missense_variant	28/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3679G>C	p.Val1227Leu	missense_variant	28/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3769G>C	p.Val1257Leu	missense_variant	28/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3769G>C	p.Val1257Leu	missense_variant	28/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3769G>C	p.Val1257Leu	missense_variant	28/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3769G>C	p.Val1257Leu	missense_variant	28/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3679G>C	p.Val1227Leu	missense_variant	28/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3754G>C	p.Val1252Leu	missense_variant	29/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3739G>C	p.Val1247Leu	missense_variant	29/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3679G>C	p.Val1227Leu	missense_variant	28/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3679G>C	p.Val1227Leu	missense_variant	28/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3679G>C	p.Val1227Leu	missense_variant	28/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3679G>C	p.Val1227Leu	missense_variant	28/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3754G>C	p.Val1252Leu	missense_variant	29/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3679G>C	p.Val1227Leu	missense_variant	28/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3679G>C	p.Val1227Leu	missense_variant	28/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3679G>C	p.Val1227Leu	missense_variant	28/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3679G>C	p.Val1227Leu	missense_variant	28/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3679G>C	p.Val1227Leu	missense_variant	28/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3679G>C	p.Val1227Leu	missense_variant	28/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3679G>C	p.Val1227Leu	missense_variant	28/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3679G>C	p.Val1227Leu	missense_variant	28/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3670G>C	p.Val1224Leu	missense_variant	28/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3679G>C	p.Val1227Leu	missense_variant	28/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*2286G>C		non_coding_transcript_exon_variant	26/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*2286G>C		3_prime_UTR_variant	26/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250764 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;.
Eigen	Benign	-0.074
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.39	T;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	0.64	D
MutationAssessor	Benign	0.85	.;.;.;.;.;.;.;.;.;.;.;L;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.41
Sift	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;.
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.051, 0.0010, 0.015, 0.012, 0.11, 0.010, 0.18, 0.11, 0.062, 0.54, 0.42	.;B;B;B;B;B;B;B;B;B;B;B;B;B;P;B;.;B;B;.;.;.;B;.
Vest4		0.48
MutPred		0.64		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at I1249 (P = 0.0017);Gain of catalytic residue at I1249 (P = 0.0017);.;.;.;.;.;.;.;.;.;.;.;
MVP		0.69
MPC		1.0
ClinPred		0.63	D
GERP RS		3.1
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373124557; hg19: chr12-2719827;