chr12-2681966-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000682544.1(CACNA1C):​c.5695A>C​(p.Met1899Leu) 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. 15/19 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. M1899V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C ENST00000682544.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.521
• Publications: 31 publications found

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]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248502 AF XY: 0.0000148

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4630

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104424

Other (OTH) AF: 0.00 AC: 0 AN: 59980

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
AlphaMissense	Benign	0.084
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
PhyloP100		-0.52
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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs10774053; hg19: chr12-2791132;