rs10774053

Positions:

• chr12-2681966-A-C
• chr12-2681966-A-G

Variant summary

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

The ENST00000327702.12(CACNA1C):​c.5461A>C​(p.Met1821Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict 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. M1821V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C ENST00000327702.12 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.521

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 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 7.2194 (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=0.07627091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5445-584A>C		intron_variant		ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5445-584A>C		intron_variant		ENST00000399603.6	NP_001161095.1
CACNA1C-AS1	NR_045725.1	n.334-4069T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5445-584A>C		intron_variant		5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.5445-584A>C		intron_variant		1	NM_000719.7	ENSP00000382563
CACNA1C-AS1	ENST00000501371.5	n.295-4069T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000805 AC: 2 AN: 248502 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135032

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452128 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 722972

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000166 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	2.7
DANN	Benign	0.44
DEOGEN2	Benign	0.0073	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0084	N
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.076	T;T
MetaSVM	Benign	-0.50	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.030	N;N
REVEL	Benign	0.17
Sift	Benign	0.89	T;T
Sift4G	Benign	0.69	T;T
Vest4		0.052
MVP		0.36
ClinPred		0.0071	T
GERP RS		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10774053; hg19: chr12-2791132;