12-2688778-C-A

Variant names:

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

Variant links:

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 links:

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

ITFG2-AS1 links:

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

CACNA1C-AS1 links:

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new If you want to explore the variant's impact on the transcript NM_000719.7, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1C	NM_000719.7	MANE Select	c.6116C>A	p.Ala2039Glu	missense splice_region	Exon 46 of 47	NP_000710.5
CACNA1C	NM_001167623.2	MANE Plus Clinical	c.6116C>A	p.Ala2039Glu	missense splice_region	Exon 46 of 47	NP_001161095.1	Q13936-37
CACNA1C	NM_199460.4		c.6365C>A	p.Ala2122Glu	missense splice_region	Exon 49 of 50	NP_955630.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.6116C>A	p.Ala2039Glu	missense splice_region	Exon 46 of 47	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.6116C>A	p.Ala2039Glu	missense splice_region	Exon 46 of 47	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1		c.6455C>A	p.Ala2152Glu	missense splice_region	Exon 49 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1366822

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

670856

African (AFR)

AF:

0.00

AC:

AN:

31156

American (AMR)

AF:

0.00

AC:

AN:

33066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21864

East Asian (EAS)

AF:

0.00

AC:

AN:

36868

South Asian (SAS)

AF:

0.00

AC:

AN:

73572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41652

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5426

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1066604

Other (OTH)

AF:

0.00

AC:

AN:

56614

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000672

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

CardioboostArm

Benign

0.039

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

1.0

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.63

MetaSVM

Benign

-0.42

PhyloP100

5.7

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

Sift4G

Benign

0.15

gMVP

0.84

Mutation Taster

=8/92

disease causing

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over