rs10774053

Variant names:

• chr12-2681966-A-C
• rs10774053
• ENST00000682544.1:c.5695A>C

Your query was ambiguous. Multiple possible variants found:

• 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 NM_199460.4(CACNA1C):​c.5605A>C​(p.Met1869Leu) 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. M1869V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_199460.4 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:):

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 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: 7.225 (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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07627091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5445-584A>C		intron_variant	Intron 42 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5445-584A>C		intron_variant	Intron 42 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000682544.1	c.5695A>C	p.Met1899Leu	missense_variant	Exon 45 of 50			ENSP00000507184.1
CACNA1C	ENST00000327702.12	c.5461A>C	p.Met1821Leu	missense_variant	Exon 43 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5461A>C	p.Met1821Leu	missense_variant	Exon 43 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000399603.6	c.5445-584A>C		intron_variant	Intron 42 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5445-584A>C		intron_variant	Intron 42 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000406454.8	c.5658-584A>C		intron_variant	Intron 43 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5625-584A>C		intron_variant	Intron 42 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5610-584A>C		intron_variant	Intron 43 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5589-584A>C		intron_variant	Intron 44 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5568-584A>C		intron_variant	Intron 42 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000682462.1	c.5535-584A>C		intron_variant	Intron 42 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5535-584A>C		intron_variant	Intron 42 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5535-584A>C		intron_variant	Intron 42 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5535-584A>C		intron_variant	Intron 42 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5529-584A>C		intron_variant	Intron 43 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5520-584A>C		intron_variant	Intron 43 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5505-584A>C		intron_variant	Intron 43 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5502-584A>C		intron_variant	Intron 42 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5502-584A>C		intron_variant	Intron 42 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5502-584A>C		intron_variant	Intron 42 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5496-584A>C		intron_variant	Intron 42 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5487-584A>C		intron_variant	Intron 42 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5469-584A>C		intron_variant	Intron 41 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5469-584A>C		intron_variant	Intron 41 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5463-584A>C		intron_variant	Intron 41 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5445-584A>C		intron_variant	Intron 42 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5445-584A>C		intron_variant	Intron 42 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5445-584A>C		intron_variant	Intron 42 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5445-584A>C		intron_variant	Intron 42 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5445-584A>C		intron_variant	Intron 42 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5436-584A>C		intron_variant	Intron 42 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5412-584A>C		intron_variant	Intron 41 of 45			ENSP00000507309.1

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
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;