Genetic Variant NM_000719.7:c.5361G>A (chr12-2679713-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000719.7(CACNA1C):c.5361G>A(p.Thr1787Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 1,608,514 control chromosomes in the GnomAD database, including 398,256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 28886 hom., cov: 34)

Exomes 𝑓: 0.71 ( 369370 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -3.82

Publications

43 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 12-2679713-G-A is Benign according to our data. Variant chr12-2679713-G-A is described in ClinVar as Benign. ClinVar VariationId is 93413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.82 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

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
CACNA1C	NM_000719.7	MANE Select	c.5361G>A	p.Thr1787Thr	synonymous	Exon 42 of 47	NP_000710.5
CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5361G>A	p.Thr1787Thr	synonymous	Exon 42 of 47	NP_001161095.1
CACNA1C	NM_199460.4		c.5505G>A	p.Thr1835Thr	synonymous	Exon 44 of 50	NP_955630.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.5361G>A	p.Thr1787Thr	synonymous	Exon 42 of 47	ENSP00000382512.1
CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5361G>A	p.Thr1787Thr	synonymous	Exon 42 of 47	ENSP00000382563.1
CACNA1C	ENST00000682544.1		c.5595G>A	p.Thr1865Thr	synonymous	Exon 44 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes

AF:

0.578

AC:

87834

AN:

152028

Hom.:

28877

Cov.:

show subpopulations

Gnomad AFR

AF:

0.236

Gnomad AMI

AF:

0.613

Gnomad AMR

AF:

0.644

Gnomad ASJ

AF:

0.672

Gnomad EAS

AF:

0.624

Gnomad SAS

AF:

0.667

Gnomad FIN

AF:

0.767

Gnomad MID

AF:

0.462

Gnomad NFE

AF:

0.726

Gnomad OTH

AF:

0.586

GnomAD2 exomes

AF:

0.677

AC:

160515

AN:

236924

AF XY:

0.683

show subpopulations

Gnomad AFR exome

AF:

0.236

Gnomad AMR exome

AF:

0.706

Gnomad ASJ exome

AF:

0.664

Gnomad EAS exome

AF:

0.624

Gnomad FIN exome

AF:

0.763

Gnomad NFE exome

AF:

0.723

Gnomad OTH exome

AF:

0.676

GnomAD4 exome

AF:

0.706

AC:

1028616

AN:

1456368

Hom.:

369370

Cov.:

AF XY:

0.706

AC XY:

511204

AN XY:

724000

show subpopulations

African (AFR)

AF:

0.211

AC:

7042

AN:

33324

American (AMR)

AF:

0.696

AC:

30584

AN:

43920

Ashkenazi Jewish (ASJ)

AF:

0.661

AC:

17162

AN:

25966

East Asian (EAS)

AF:

0.598

AC:

23611

AN:

39470

South Asian (SAS)

AF:

0.657

AC:

56201

AN:

85508

European-Finnish (FIN)

AF:

0.758

AC:

40148

AN:

52972

Middle Eastern (MID)

AF:

0.511

AC:

2946

AN:

5762

European-Non Finnish (NFE)

AF:

0.731

AC:

810544

AN:

1109268

Other (OTH)

AF:

0.671

AC:

40378

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

16487

32973

49460

65946

82433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19846

39692

59538

79384

99230

<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

AF:

0.577

AC:

87853

AN:

152146

Hom.:

28886

Cov.:

AF XY:

0.581

AC XY:

43218

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.236

AC:

9782

AN:

41508

American (AMR)

AF:

0.644

AC:

9847

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.672

AC:

2333

AN:

3470

East Asian (EAS)

AF:

0.623

AC:

3211

AN:

5152

South Asian (SAS)

AF:

0.666

AC:

3212

AN:

4824

European-Finnish (FIN)

AF:

0.767

AC:

8132

AN:

10602

Middle Eastern (MID)

AF:

0.483

AC:

142

AN:

294

European-Non Finnish (NFE)

AF:

0.727

AC:

49390

AN:

67982

Other (OTH)

AF:

0.589

AC:

1245

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1580

3161

4741

6322

7902

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

718

1436

2154

2872

3590

<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:

0.675

Hom.:

21008

Bravo

AF:

0.553

Asia WGS

AF:

0.637

AC:

2211

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 10, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

May 13, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Timothy syndrome

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Long QT syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Sep 04, 2015

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0040

(source)

DANN

Benign

0.90

PhyloP100

-3.8

Mutation Taster

=89/11

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over