12-2685771-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000719.7(CACNA1C):c.5609C>T(p.Thr1870Met) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1870K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.01

Publications

23 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057109594).

BP6

Variant 12-2685771-C-T is Benign according to our data. Variant chr12-2685771-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.5948C>T	p.Thr1983Met	missense_variant	Exon 47 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.5822C>T	p.Thr1941Met	missense_variant	Exon 45 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.5789C>T	p.Thr1930Met	missense_variant	Exon 44 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.5774C>T	p.Thr1925Met	missense_variant	Exon 45 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.5753C>T	p.Thr1918Met	missense_variant	Exon 46 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.5732C>T	p.Thr1911Met	missense_variant	Exon 44 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.5714C>T	p.Thr1905Met	missense_variant	Exon 45 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.5714C>T	p.Thr1905Met	missense_variant	Exon 45 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.5699C>T	p.Thr1900Met	missense_variant	Exon 44 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.5699C>T	p.Thr1900Met	missense_variant	Exon 44 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.5699C>T	p.Thr1900Met	missense_variant	Exon 44 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.5699C>T	p.Thr1900Met	missense_variant	Exon 44 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.5693C>T	p.Thr1898Met	missense_variant	Exon 45 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.5684C>T	p.Thr1895Met	missense_variant	Exon 45 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.5669C>T	p.Thr1890Met	missense_variant	Exon 45 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.5666C>T	p.Thr1889Met	missense_variant	Exon 44 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.5666C>T	p.Thr1889Met	missense_variant	Exon 44 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.5666C>T	p.Thr1889Met	missense_variant	Exon 44 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.5660C>T	p.Thr1887Met	missense_variant	Exon 44 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.5651C>T	p.Thr1884Met	missense_variant	Exon 44 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.5633C>T	p.Thr1878Met	missense_variant	Exon 43 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.5633C>T	p.Thr1878Met	missense_variant	Exon 43 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.5627C>T	p.Thr1876Met	missense_variant	Exon 43 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.5600C>T	p.Thr1867Met	missense_variant	Exon 44 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.5576C>T	p.Thr1859Met	missense_variant	Exon 43 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

145

AN:

141892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000696

Gnomad ASJ

AF:

0.000309

Gnomad EAS

AF:

0.00187

Gnomad SAS

AF:

0.00153

Gnomad FIN

AF:

0.00209

Gnomad MID

AF:

0.00360

Gnomad NFE

AF:

0.000863

Gnomad OTH

AF:

0.000526

GnomAD2 exomes

AF:

0.00102

AC:

252

AN:

246240

AF XY:

0.000942

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000676

Gnomad FIN exome

AF:

0.00697

Gnomad NFE exome

AF:

0.000394

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000658

AC:

946

AN:

1437826

Hom.:

Cov.:

AF XY:

0.000654

AC XY:

468

AN XY:

715836

show subpopulations

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

African (AFR)

AF:

0.000182

AC:

AN:

32974

American (AMR)

AF:

0.000384

AC:

AN:

44236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25912

East Asian (EAS)

AF:

0.000738

AC:

AN:

39316

South Asian (SAS)

AF:

0.000902

AC:

AN:

85330

European-Finnish (FIN)

AF:

0.00517

AC:

269

AN:

52050

Middle Eastern (MID)

AF:

0.000363

AC:

AN:

5514

European-Non Finnish (NFE)

AF:

0.000467

AC:

510

AN:

1093058

Other (OTH)

AF:

0.000606

AC:

AN:

59436

⚠️ 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: 0.346

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00102

AC:

145

AN:

142000

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

69258

show subpopulations

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

African (AFR)

AF:

0.00106

AC:

AN:

38660

American (AMR)

AF:

0.000695

AC:

AN:

14390

Ashkenazi Jewish (ASJ)

AF:

0.000309

AC:

AN:

3236

East Asian (EAS)

AF:

0.00188

AC:

AN:

4796

South Asian (SAS)

AF:

0.00153

AC:

AN:

4580

European-Finnish (FIN)

AF:

0.00209

AC:

AN:

9568

Middle Eastern (MID)

AF:

0.00388

AC:

AN:

258

European-Non Finnish (NFE)

AF:

0.000863

AC:

AN:

63732

Other (OTH)

AF:

0.000522

AC:

AN:

1916

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.330

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.0938

Hom.:

3188

ExAC

AF:

0.00352

AC:

426

EpiCase

AF:

0.000439

EpiControl

AF:

0.000357

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 26, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.5609C>T (p.Thr1870Met) in CACNA1C gene is a missense change that involves a highly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant of interest is located outside of any known functional domain, although the functional impact of this missense change is yet to be studied. The variant is present in the large control population dataset of ExAC at a frequency 0.003 (359/119184 chrs tested, including 1 homozygote), which exceeds the maximal expected frequency of a pathogenic allele (0.00001) in this gene. The variant has been reported in multiple affected individuals as well as in numerous unaffected controls. Lastly, it has been reported as Benign by several reputable databases/clinical laboratories. Taken together, the variant was classified as Benign. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30403697, 27920829) -

not specified

Benign:3

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Feb 15, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

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

Eigen

Benign

0.18

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.99

MetaRNN

Benign

0.0057

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

MetaSVM

Benign

-0.73

PhyloP100

6.0

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.4

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.

REVEL

Benign

0.15

Sift

Benign

0.10

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

Sift4G

Benign

0.23

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

Polyphen

0.99, 0.32, 0.97, 0.64, 0.99, 0.87, 0.48, 0.99, 0.78, 0.92, 0.98, 0.99, 0.93

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

Vest4

0.49

MVP

0.52

MPC

0.33

ClinPred

0.029

GERP RS

4.3

gMVP

0.39

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over