rs1184709095

Variant names:

• chr12-2610703-A-G
• rs1184709095
• NM_000719.7:c.3717+4A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3867+4A>G		splice_region_variant, intron_variant	Intron 29 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3882+4A>G		splice_region_variant, intron_variant	Intron 29 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3777+4A>G		splice_region_variant, intron_variant	Intron 29 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3807+4A>G		splice_region_variant, intron_variant	Intron 28 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3807+4A>G		splice_region_variant, intron_variant	Intron 28 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3807+4A>G		splice_region_variant, intron_variant	Intron 28 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3807+4A>G		splice_region_variant, intron_variant	Intron 28 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3792+4A>G		splice_region_variant, intron_variant	Intron 29 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3777+4A>G		splice_region_variant, intron_variant	Intron 29 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3792+4A>G		splice_region_variant, intron_variant	Intron 29 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3708+4A>G		splice_region_variant, intron_variant	Intron 28 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3717+4A>G		splice_region_variant, intron_variant	Intron 28 of 45			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*2324+4A>G		splice_region_variant, intron_variant	Intron 26 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152258 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250384 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111928

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74378

African (AFR) AF: 0.0000241 AC: 1 AN: 41476

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1

Aug 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Uncertain:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	19
DANN	Benign	0.92
PhyloP100		5.0

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

Other links and lift over

dbSNP: rs1184709095; hg19: chr12-2719869;