12-2690975-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000719.7(CACNA1C):c.6193G>T(p.Asp2065Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D2065N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.97

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:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CACNA1C
• BP4: Computational evidence support a benign effect (MetaRNN=0.33757067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.6193G>T	p.Asp2065Tyr	missense_variant	47/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.6193G>T	p.Asp2065Tyr	missense_variant	47/47	ENST00000399603.6
CACNA1C-AS1	NR_045725.1	n.94C>A		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6193G>T	p.Asp2065Tyr	missense_variant	47/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.6193G>T	p.Asp2065Tyr	missense_variant	47/47	1	NM_000719.7
CACNA1C-AS1	ENST00000501371.5	n.55C>A		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Benign	0.0046
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.086	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.34	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	-0.11	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.1	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.45
Sift	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;.
Sift4G	Pathogenic	0.0010	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, 0.98, 0.064	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;B;.
Vest4		0.50
MVP		0.64
MPC		0.33
ClinPred		1.0	D
GERP RS		3.7
gMVP		0.94

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: rs1060503451; hg19: chr12-2800141;