12-2601850-G-A

Variant names:

• chr12-2601850-G-A
• rs113929946
• NM_000719.7:c.2854-4G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000719.7(CACNA1C):​c.2854-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000934 in 1,605,958 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: CACNA1C NM_000719.7 splice_region, intron
• Scores: Splicing: ADA: 0.000008419
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.617
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 12-2601850-G-A is Benign according to our data. Variant chr12-2601850-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 496072.
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3004-4G>A		splice_region_variant, intron_variant	Intron 22 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3019-4G>A		splice_region_variant, intron_variant	Intron 22 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2914-4G>A		splice_region_variant, intron_variant	Intron 22 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2944-4G>A		splice_region_variant, intron_variant	Intron 21 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2944-4G>A		splice_region_variant, intron_variant	Intron 21 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2944-4G>A		splice_region_variant, intron_variant	Intron 21 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2944-4G>A		splice_region_variant, intron_variant	Intron 21 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2929-4G>A		splice_region_variant, intron_variant	Intron 22 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2914-4G>A		splice_region_variant, intron_variant	Intron 22 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2929-4G>A		splice_region_variant, intron_variant	Intron 22 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2845-4G>A		splice_region_variant, intron_variant	Intron 21 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2854-4G>A		splice_region_variant, intron_variant	Intron 21 of 45			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1461-4G>A		splice_region_variant, intron_variant	Intron 19 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000719 AC: 18 AN: 250246 AF XY: 0.0000737

Gnomad AFR exome AF: 0.0000636

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000963 AC: 140 AN: 1453738 Hom.: 0 Cov.: 29 AF XY: 0.0000939 AC XY: 68 AN XY: 723800

African (AFR) AF: 0.0000300 AC: 1 AN: 33292

American (AMR) AF: 0.0000447 AC: 2 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000121 AC: 134 AN: 1104724

Other (OTH) AF: 0.0000500 AC: 3 AN: 60058

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74358

African (AFR) AF: 0.0000965 AC: 4 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000226 Hom.: 0

Bravo AF: 0.0000907

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Jan 16, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CACNA1C c.2854-4G>A variant involves the alteration of a non-conserved intronic nucleotide, which 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 7/120806 (1/17259), predominantly in the European (Non-Finnish) cohort, 6/66684 (1/11113), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic CACNA1C variant of 1/100000. Therefore, suggesting this variant is likely a benign polymorphism found in population(s) of European (Non-Finnish) origin. The variant of interest has, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, due to the frequency observed in the ExAC control population, the variant of interest has been classified as Benign. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Timothy syndrome;C2678478:Brugada syndrome 3;C5774213:Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;CN260585:Long qt syndrome 8 Uncertain:1

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C NM_000719.6 exon 22 c.2854-4G>A: This variant has not been reported in the literature and is present in 0.01% (4/24432) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-2711016-G-A). This variant is present in ClinVar (Variation ID:496072). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain -

CACNA1C-related disorder Benign:1

Feb 23, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Long QT syndrome Benign:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Apr 20, 2018

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	-0.58
CADD	Benign	9.4
DANN	Benign	0.54
PhyloP100		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000084
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs113929946; hg19: chr12-2711016;