12-2688778-C-T

Position:

chr12-2688778-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_000719.7(CACNA1C):c.6116C>T(p.Ala2039Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000461 in 1,518,952 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to 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 Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense, splice_region

Scores

Splicing: ADA: 0.9879

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.71

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:

CACNA1C-AS1 (HGNC:):

CACNA1C-AS1 links:

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

CACNA1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

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: 7.2674 (greater than threshold 3.09). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. GenCC has associacion of the 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.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.6116C>T	p.Ala2039Val	missense_variant, splice_region_variant	46/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.6116C>T	p.Ala2039Val	missense_variant, splice_region_variant	46/47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.6116C>T	p.Ala2039Val	missense_variant, splice_region_variant	46/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.6116C>T	p.Ala2039Val	missense_variant, splice_region_variant	46/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.6455C>T	p.Ala2152Val	missense_variant, splice_region_variant	49/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.6329C>T	p.Ala2110Val	missense_variant, splice_region_variant	47/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.6296C>T	p.Ala2099Val	missense_variant, splice_region_variant	46/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.6281C>T	p.Ala2094Val	missense_variant, splice_region_variant	47/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.6260C>T	p.Ala2087Val	missense_variant, splice_region_variant	48/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.6239C>T	p.Ala2080Val	missense_variant, splice_region_variant	46/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.6221C>T	p.Ala2074Val	missense_variant, splice_region_variant	47/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.6221C>T	p.Ala2074Val	missense_variant, splice_region_variant	47/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.6206C>T	p.Ala2069Val	missense_variant, splice_region_variant	46/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.6206C>T	p.Ala2069Val	missense_variant, splice_region_variant	46/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.6206C>T	p.Ala2069Val	missense_variant, splice_region_variant	46/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.6206C>T	p.Ala2069Val	missense_variant, splice_region_variant	46/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.6200C>T	p.Ala2067Val	missense_variant, splice_region_variant	47/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.6191C>T	p.Ala2064Val	missense_variant, splice_region_variant	47/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.6176C>T	p.Ala2059Val	missense_variant, splice_region_variant	47/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.6173C>T	p.Ala2058Val	missense_variant, splice_region_variant	46/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.6173C>T	p.Ala2058Val	missense_variant, splice_region_variant	46/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.6173C>T	p.Ala2058Val	missense_variant, splice_region_variant	46/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.6167C>T	p.Ala2056Val	missense_variant, splice_region_variant	46/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.6158C>T	p.Ala2053Val	missense_variant, splice_region_variant	46/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.6140C>T	p.Ala2047Val	missense_variant, splice_region_variant	45/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.6140C>T	p.Ala2047Val	missense_variant, splice_region_variant	45/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.6134C>T	p.Ala2045Val	missense_variant, splice_region_variant	45/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.6116C>T	p.Ala2039Val	missense_variant, splice_region_variant	46/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.6116C>T	p.Ala2039Val	missense_variant, splice_region_variant	46/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.6116C>T	p.Ala2039Val	missense_variant, splice_region_variant	46/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.6116C>T	p.Ala2039Val	missense_variant, splice_region_variant	46/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.6116C>T	p.Ala2039Val	missense_variant, splice_region_variant	46/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.6107C>T	p.Ala2036Val	missense_variant, splice_region_variant	46/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.6083C>T	p.Ala2028Val	missense_variant, splice_region_variant	45/46			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000439

AC:

AN:

1366822

Hom.:

Cov.:

AF XY:

0.00000596

AC XY:

AN XY:

670856

show subpopulations

Gnomad4 AFR exome

AF:

0.0000321

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:

0.00000469

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000849

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.035

T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

1.0

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.43

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.043

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.

REVEL

Uncertain

0.42

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

Uncertain

0.014

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 0.94, 0.31, 0.069, 1.0, 0.20

.;D;P;B;B;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;D;.

Vest4

0.78

MVP

0.47

MPC

0.75

ClinPred

1.0

GERP RS

5.4

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over