12-2593261-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000719.7(CACNA1C):c.2579G>T(p.Arg860Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R860Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.08

Publications

0 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 Gene-Disease associations (from GenCC):

Timothy syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
long QT syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
long QT syndrome 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
Brugada syndrome 3
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
short QT syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000719.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-2593261-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190654.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.2669G>T	p.Arg890Leu	missense_variant	Exon 19 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.2744G>T	p.Arg915Leu	missense_variant	Exon 20 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.2669G>T	p.Arg890Leu	missense_variant	Exon 19 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.2669G>T	p.Arg890Leu	missense_variant	Exon 19 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.2669G>T	p.Arg890Leu	missense_variant	Exon 19 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.2669G>T	p.Arg890Leu	missense_variant	Exon 19 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.2654G>T	p.Arg885Leu	missense_variant	Exon 20 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.2654G>T	p.Arg885Leu	missense_variant	Exon 20 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.2570G>T	p.Arg857Leu	missense_variant	Exon 19 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.2579G>T	p.Arg860Leu	missense_variant	Exon 19 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*1186G>T		non_coding_transcript_exon_variant	Exon 17 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*1186G>T		3_prime_UTR_variant	Exon 17 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461402

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726924

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111774

Other (OTH)

AF:

0.00

AC:

AN:

60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

CardioboostArm

Uncertain

0.28

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.088

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

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.87

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.0

.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.

PhyloP100

8.1

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.4

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

REVEL

Pathogenic

0.81

Sift

Uncertain

0.019

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

Sift4G

Benign

0.14

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

Vest4

0.84

ClinPred

1.0

GERP RS

4.9

gMVP

0.87

Mutation Taster

=11/89

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over