rs549476254

Variant names:

• chr12-2688778-C-A
• rs549476254
• NM_000719.7:c.6116C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2688778-C-A
• chr12-2688778-C-G
• chr12-2688778-C-T

Variant summary

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

The NM_000719.7(CACNA1C):​c.6116C>A​(p.Ala2039Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A2039G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense, splice_region
• Scores: Splicing: ADA: 0.9299
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.71
• Publications: 5 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6116C>A	p.Ala2039Glu	missense_variant, splice_region_variant	Exon 46 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6116C>A	p.Ala2039Glu	missense_variant, splice_region_variant	Exon 46 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6116C>A	p.Ala2039Glu	missense_variant, splice_region_variant	Exon 46 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6116C>A	p.Ala2039Glu	missense_variant, splice_region_variant	Exon 46 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6455C>A	p.Ala2152Glu	missense_variant, splice_region_variant	Exon 49 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6329C>A	p.Ala2110Glu	missense_variant, splice_region_variant	Exon 47 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6296C>A	p.Ala2099Glu	missense_variant, splice_region_variant	Exon 46 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6281C>A	p.Ala2094Glu	missense_variant, splice_region_variant	Exon 47 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6260C>A	p.Ala2087Glu	missense_variant, splice_region_variant	Exon 48 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6239C>A	p.Ala2080Glu	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6221C>A	p.Ala2074Glu	missense_variant, splice_region_variant	Exon 47 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6221C>A	p.Ala2074Glu	missense_variant, splice_region_variant	Exon 47 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6206C>A	p.Ala2069Glu	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6206C>A	p.Ala2069Glu	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6206C>A	p.Ala2069Glu	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6206C>A	p.Ala2069Glu	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6200C>A	p.Ala2067Glu	missense_variant, splice_region_variant	Exon 47 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6191C>A	p.Ala2064Glu	missense_variant, splice_region_variant	Exon 47 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6176C>A	p.Ala2059Glu	missense_variant, splice_region_variant	Exon 47 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6173C>A	p.Ala2058Glu	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6173C>A	p.Ala2058Glu	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6173C>A	p.Ala2058Glu	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6167C>A	p.Ala2056Glu	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6158C>A	p.Ala2053Glu	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6140C>A	p.Ala2047Glu	missense_variant, splice_region_variant	Exon 45 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6140C>A	p.Ala2047Glu	missense_variant, splice_region_variant	Exon 45 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6134C>A	p.Ala2045Glu	missense_variant, splice_region_variant	Exon 45 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6116C>A	p.Ala2039Glu	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6116C>A	p.Ala2039Glu	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6116C>A	p.Ala2039Glu	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6116C>A	p.Ala2039Glu	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6116C>A	p.Ala2039Glu	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6107C>A	p.Ala2036Glu	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6083C>A	p.Ala2028Glu	missense_variant, splice_region_variant	Exon 45 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1366822 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 670856

African (AFR) AF: 0.00 AC: 0 AN: 31156

American (AMR) AF: 0.00 AC: 0 AN: 33066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21864

East Asian (EAS) AF: 0.00 AC: 0 AN: 36868

South Asian (SAS) AF: 0.00 AC: 0 AN: 73572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5426

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1066604

Other (OTH) AF: 0.00 AC: 0 AN: 56614

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000672 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostArm	Benign	0.039
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
PhyloP100		5.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;D;T
Polyphen		1.0, 0.89, 0.97, 0.99, 1.0, 0.95, 0.99, 1.0, 0.99	.;D;P;D;D;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D;.
Vest4		0.84
MVP		0.51
MPC		0.82
ClinPred		0.99	D
GERP RS		5.4
gMVP		0.84
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Benign	0.57
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

Other links and lift over

dbSNP: rs549476254; hg19: chr12-2797944; COSMIC: COSV59708098; COSMIC: COSV59708098;