chr12-2610703-A-G

Position:

chr12-2610703-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000719.7(CACNA1C):c.3717+4A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000248 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 splice_region, intron

Scores

Splicing: ADA: 0.4553

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.3717+4A>G		splice_region_variant, intron_variant		ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.3717+4A>G		splice_region_variant, intron_variant		ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.3717+4A>G	splice_region_variant, intron_variant	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.3717+4A>G	splice_region_variant, intron_variant	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.3867+4A>G	splice_region_variant, intron_variant			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.3717+4A>G	splice_region_variant, intron_variant	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.3717+4A>G	splice_region_variant, intron_variant	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.3882+4A>G	splice_region_variant, intron_variant			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.3777+4A>G	splice_region_variant, intron_variant	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.3717+4A>G	splice_region_variant, intron_variant	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.3807+4A>G	splice_region_variant, intron_variant			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.3807+4A>G	splice_region_variant, intron_variant			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.3807+4A>G	splice_region_variant, intron_variant			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.3807+4A>G	splice_region_variant, intron_variant			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.3792+4A>G	splice_region_variant, intron_variant	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.3777+4A>G	splice_region_variant, intron_variant	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.3792+4A>G	splice_region_variant, intron_variant			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.3717+4A>G	splice_region_variant, intron_variant	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.3717+4A>G	splice_region_variant, intron_variant			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.3708+4A>G	splice_region_variant, intron_variant			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.3717+4A>G	splice_region_variant, intron_variant			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000480911.6 link	n.*2324+4A>G	splice_region_variant, intron_variant	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250384

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135578

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 23, 2021

- -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2024

This sequence change falls in intron 28 of the CACNA1C gene. It does not directly change the encoded amino acid sequence of the CACNA1C protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 526999). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2024

The c.3717+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 28 in the CACNA1C gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. According to data from gnomAD, the frequency for this variant is above the maximum credible frequency for a cardiac disease-causing variant in this gene based on internally established thresholds (Karczewski et al.Nature. 2020 May;581(7809):434-443; Whiffin et al.Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration withCACNA1C-related neurodevelopmental disorderis unknown; however, the association withCACNA1C-related long QT syndrome/Timothy syndromeis unlikely. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.46

dbscSNV1_RF

Benign

0.34

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over