12-2679461-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_000719.7(CACNA1C):c.5109C>T(p.Phe1703Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000492 in 1,423,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0920

Publications

1 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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 12-2679461-C-T is Benign according to our data. Variant chr12-2679461-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 527028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.092 with no splicing effect.

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5109C>T	p.Phe1703Phe	synonymous_variant	Exon 42 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.5109C>T	p.Phe1703Phe	synonymous_variant	Exon 42 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.5109C>T	p.Phe1703Phe	synonymous_variant	Exon 42 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.5109C>T	p.Phe1703Phe	synonymous_variant	Exon 42 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.5343C>T	p.Phe1781Phe	synonymous_variant	Exon 44 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.5109C>T	p.Phe1703Phe	synonymous_variant	Exon 42 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.5076C>T	p.Phe1692Phe	synonymous_variant	Exon 41 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.5274C>T	p.Phe1758Phe	synonymous_variant	Exon 43 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.5253C>T	p.Phe1751Phe	synonymous_variant	Exon 44 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.5232C>T	p.Phe1744Phe	synonymous_variant	Exon 42 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.5109C>T	p.Phe1703Phe	synonymous_variant	Exon 42 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.5109C>T	p.Phe1703Phe	synonymous_variant	Exon 42 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.5199C>T	p.Phe1733Phe	synonymous_variant	Exon 42 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.5199C>T	p.Phe1733Phe	synonymous_variant	Exon 42 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.5199C>T	p.Phe1733Phe	synonymous_variant	Exon 42 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.5199C>T	p.Phe1733Phe	synonymous_variant	Exon 42 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.5193C>T	p.Phe1731Phe	synonymous_variant	Exon 43 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.5184C>T	p.Phe1728Phe	synonymous_variant	Exon 43 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.5169C>T	p.Phe1723Phe	synonymous_variant	Exon 43 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.5166C>T	p.Phe1722Phe	synonymous_variant	Exon 42 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.5166C>T	p.Phe1722Phe	synonymous_variant	Exon 42 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.5166C>T	p.Phe1722Phe	synonymous_variant	Exon 42 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.5160C>T	p.Phe1720Phe	synonymous_variant	Exon 42 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.5151C>T	p.Phe1717Phe	synonymous_variant	Exon 42 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.5133C>T	p.Phe1711Phe	synonymous_variant	Exon 41 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.5133C>T	p.Phe1711Phe	synonymous_variant	Exon 41 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.5127C>T	p.Phe1709Phe	synonymous_variant	Exon 41 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.5109C>T	p.Phe1703Phe	synonymous_variant	Exon 42 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.5109C>T	p.Phe1703Phe	synonymous_variant	Exon 42 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.5109C>T	p.Phe1703Phe	synonymous_variant	Exon 42 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.5109C>T	p.Phe1703Phe	synonymous_variant	Exon 42 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.5109C>T	p.Phe1703Phe	synonymous_variant	Exon 42 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.5100C>T	p.Phe1700Phe	synonymous_variant	Exon 42 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.5076C>T	p.Phe1692Phe	synonymous_variant	Exon 41 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000959

AC:

AN:

208594

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000613

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000492

AC:

AN:

1423846

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703652

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32724

American (AMR)

AF:

0.00

AC:

AN:

41698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23982

East Asian (EAS)

AF:

0.0000259

AC:

AN:

38646

South Asian (SAS)

AF:

0.00

AC:

AN:

79638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00000458

AC:

AN:

1091646

Other (OTH)

AF:

0.0000170

AC:

AN:

58786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.411

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Benign:1

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 19, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.8

(source)

DANN

Benign

0.87

PhyloP100

-0.092

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over