chr12-2414189-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000719.7(CACNA1C):c.478-34787A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 152,026 control chromosomes in the GnomAD database, including 9,257 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.34 ( 9257 hom., cov: 32)

Consequence

CACNA1C
NM_000719.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0240

Publications

19 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.478-34787A>G		intron_variant	Intron 3 of 46	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.478-34787A>G		intron_variant	Intron 3 of 46	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.478-34787A>G	intron_variant	Intron 3 of 46	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.478-34787A>G	intron_variant	Intron 3 of 46	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.568-34787A>G	intron_variant	Intron 3 of 49			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.478-34787A>G	intron_variant	Intron 3 of 47	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.478-34787A>G	intron_variant	Intron 3 of 46	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.568-34787A>G	intron_variant	Intron 3 of 47			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.478-34787A>G	intron_variant	Intron 3 of 48	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.478-34787A>G	intron_variant	Intron 3 of 46	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.478-34787A>G	intron_variant	Intron 3 of 47	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.478-34787A>G	intron_variant	Intron 3 of 47	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.568-34787A>G	intron_variant	Intron 3 of 46			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.568-34787A>G	intron_variant	Intron 3 of 46			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.568-34787A>G	intron_variant	Intron 3 of 46			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.568-34787A>G	intron_variant	Intron 3 of 46			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.478-34787A>G	intron_variant	Intron 3 of 47	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.478-34787A>G	intron_variant	Intron 3 of 47	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.478-34787A>G	intron_variant	Intron 3 of 47	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.478-34787A>G	intron_variant	Intron 3 of 46	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.478-34787A>G	intron_variant	Intron 3 of 46	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.478-34787A>G	intron_variant	Intron 3 of 46	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.478-34787A>G	intron_variant	Intron 3 of 46	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.478-34787A>G	intron_variant	Intron 3 of 46			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.478-34787A>G	intron_variant	Intron 3 of 45	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.478-34787A>G	intron_variant	Intron 3 of 45	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.478-34787A>G	intron_variant	Intron 3 of 45	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.478-34787A>G	intron_variant	Intron 3 of 46	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.478-34787A>G	intron_variant	Intron 3 of 46	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.478-34787A>G	intron_variant	Intron 3 of 46	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.478-34787A>G	intron_variant	Intron 3 of 46	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.478-34787A>G	intron_variant	Intron 3 of 46			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.478-34787A>G	intron_variant	Intron 3 of 46			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.478-34787A>G	intron_variant	Intron 3 of 45			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000682152.1 link	c.427-34787A>G	intron_variant	Intron 2 of 5			ENSP00000506759.1	A0A804HHT8
CACNA1C	ENST00000480911.6 link	n.478-34787A>G	intron_variant	Intron 3 of 26	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.341

AC:

51866

AN:

151908

Hom.:

9250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.237

Gnomad AMI

AF:

0.332

Gnomad AMR

AF:

0.473

Gnomad ASJ

AF:

0.412

Gnomad EAS

AF:

0.307

Gnomad SAS

AF:

0.401

Gnomad FIN

AF:

0.365

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.366

Gnomad OTH

AF:

0.364

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.341

AC:

51893

AN:

152026

Hom.:

9257

Cov.:

AF XY:

0.344

AC XY:

25587

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.237

AC:

9817

AN:

41484

American (AMR)

AF:

0.474

AC:

7242

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.412

AC:

1432

AN:

3472

East Asian (EAS)

AF:

0.308

AC:

1589

AN:

5164

South Asian (SAS)

AF:

0.401

AC:

1927

AN:

4808

European-Finnish (FIN)

AF:

0.365

AC:

3848

AN:

10538

Middle Eastern (MID)

AF:

0.327

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.366

AC:

24875

AN:

67960

Other (OTH)

AF:

0.363

AC:

764

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1744

3488

5233

6977

8721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.353

Hom.:

16255

Bravo

AF:

0.344

Asia WGS

AF:

0.357

AC:

1244

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.6

(source)

DANN

Benign

0.38

PhyloP100

0.024

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over