rs113929946

Positions:

• chr12-2601850-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 496072.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}. Variant chr12-2601850-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2854-4G>A		splice_region_variant, intron_variant		ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2854-4G>A		splice_region_variant, intron_variant		ENST00000399603.6	NP_001161095.1

Ensembl

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

GnomAD3 exomes AF: 0.0000719 AC: 18 AN: 250246 Hom.: 0 AF XY: 0.0000737 AC XY: 10 AN XY: 135602

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 SAS 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

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000447

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: 0.000121

Gnomad4 OTH exome AF: 0.0000500

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

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

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

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 16, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs113929946; hg19: chr12-2711016;