chr12-2378773-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.478-70203A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 145,942 control chromosomes in the GnomAD database, including 9,774 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 0.37 ( 9774 hom., cov: 31)

Consequence

CACNA1C
NM_000719.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.11

Publications

6 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 (NFE) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.478-70203A>G		intron_variant	Intron 3 of 46	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.478-70203A>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.478-70203A>G	intron_variant	Intron 3 of 46	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.478-70203A>G	intron_variant	Intron 3 of 46	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.568-70203A>G	intron_variant	Intron 3 of 49			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.478-70203A>G	intron_variant	Intron 3 of 47	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.478-70203A>G	intron_variant	Intron 3 of 46	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.568-70203A>G	intron_variant	Intron 3 of 47			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.478-70203A>G	intron_variant	Intron 3 of 48	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.478-70203A>G	intron_variant	Intron 3 of 46	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.478-70203A>G	intron_variant	Intron 3 of 47	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.478-70203A>G	intron_variant	Intron 3 of 47	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.568-70203A>G	intron_variant	Intron 3 of 46			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.568-70203A>G	intron_variant	Intron 3 of 46			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.568-70203A>G	intron_variant	Intron 3 of 46			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.568-70203A>G	intron_variant	Intron 3 of 46			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.478-70203A>G	intron_variant	Intron 3 of 47	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.478-70203A>G	intron_variant	Intron 3 of 47	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.478-70203A>G	intron_variant	Intron 3 of 47	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.478-70203A>G	intron_variant	Intron 3 of 46	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.478-70203A>G	intron_variant	Intron 3 of 46	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.478-70203A>G	intron_variant	Intron 3 of 46	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.478-70203A>G	intron_variant	Intron 3 of 46	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.478-70203A>G	intron_variant	Intron 3 of 46			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.478-70203A>G	intron_variant	Intron 3 of 45	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.478-70203A>G	intron_variant	Intron 3 of 45	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.478-70203A>G	intron_variant	Intron 3 of 45	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.478-70203A>G	intron_variant	Intron 3 of 46	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.478-70203A>G	intron_variant	Intron 3 of 46	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.478-70203A>G	intron_variant	Intron 3 of 46	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.478-70203A>G	intron_variant	Intron 3 of 46	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.478-70203A>G	intron_variant	Intron 3 of 46			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.478-70203A>G	intron_variant	Intron 3 of 46			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.478-70203A>G	intron_variant	Intron 3 of 45			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000682152.1 link	c.427-70203A>G	intron_variant	Intron 2 of 5			ENSP00000506759.1	A0A804HHT8
CACNA1C	ENST00000480911.6 link	n.478-70203A>G	intron_variant	Intron 3 of 26	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.368

AC:

53658

AN:

145826

Hom.:

9765

Cov.:

show subpopulations

Gnomad AFR

AF:

0.312

Gnomad AMI

AF:

0.444

Gnomad AMR

AF:

0.345

Gnomad ASJ

AF:

0.342

Gnomad EAS

AF:

0.281

Gnomad SAS

AF:

0.281

Gnomad FIN

AF:

0.389

Gnomad MID

AF:

0.350

Gnomad NFE

AF:

0.415

Gnomad OTH

AF:

0.360

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

GnomAD4 genome

AF:

0.368

AC:

53704

AN:

145942

Hom.:

9774

Cov.:

AF XY:

0.364

AC XY:

25852

AN XY:

71056

show subpopulations

African (AFR)

AF:

0.313

AC:

12187

AN:

38956

American (AMR)

AF:

0.345

AC:

5040

AN:

14628

Ashkenazi Jewish (ASJ)

AF:

0.342

AC:

1157

AN:

3384

East Asian (EAS)

AF:

0.280

AC:

1368

AN:

4892

South Asian (SAS)

AF:

0.281

AC:

1249

AN:

4444

European-Finnish (FIN)

AF:

0.389

AC:

3886

AN:

9988

Middle Eastern (MID)

AF:

0.358

AC:

101

AN:

282

European-Non Finnish (NFE)

AF:

0.415

AC:

27598

AN:

66462

Other (OTH)

AF:

0.359

AC:

725

AN:

2020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1717

3434

5150

6867

8584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.378

Hom.:

14274

Bravo

AF:

0.351

Asia WGS

AF:

0.274

AC:

956

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.14

(source)

DANN

Benign

0.66

PhyloP100

-1.1

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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chr12-2378773-A-G

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