12-2115224-G-C

Variant names:

• chr12-2115224-G-C
• rs747083495
• NM_000719.7:c.50G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000719.7(CACNA1C):​c.50G>C​(p.Gly17Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,404,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.140G>C	p.Gly47Ala	missense_variant, splice_region_variant	Exon 2 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.140G>C	p.Gly47Ala	missense_variant, splice_region_variant	Exon 2 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.140G>C	p.Gly47Ala	missense_variant, splice_region_variant	Exon 2 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.140G>C	p.Gly47Ala	missense_variant, splice_region_variant	Exon 2 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.140G>C	p.Gly47Ala	missense_variant, splice_region_variant	Exon 2 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.140G>C	p.Gly47Ala	missense_variant, splice_region_variant	Exon 2 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.50G>C	p.Gly17Ala	missense_variant, splice_region_variant	Exon 2 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.50G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000682152.1	c.-2G>C		5_prime_UTR_variant	Exon 1 of 6			ENSP00000506759.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1404104 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 691562

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31968

American (AMR) AF: 0.00 AC: 0 AN: 38856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23380

East Asian (EAS) AF: 0.00 AC: 0 AN: 37802

South Asian (SAS) AF: 0.00 AC: 0 AN: 77040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1081728

Other (OTH) AF: 0.00 AC: 0 AN: 57906

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Oct 21, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with alanine at codon 17 of the CACNA1C protein (p.Gly17Ala). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and alanine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with CACNA1C-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
CardioboostArm	Benign	0.025
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
PhyloP100		8.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.6	D;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.017	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;T;D;T;D;D;T;D;T;T;D;D;T;T;D;T;T;T;D;T;D;T;T;T
Polyphen		0.82, 0.12, 0.97, 0.93, 1.0, 0.60, 1.0	.;.;P;.;B;P;D;P;P;D;P;P;D;P;P;D;D;.;D;P;.;.;.;.
Vest4		0.55, 0.58, 0.58, 0.60, 0.57, 0.54, 0.57, 0.57, 0.58, 0.59, 0.59, 0.54, 0.58, 0.59, 0.59, 0.55, 0.55, 0.56, 0.54, 0.60
MutPred		0.35		.;Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);
MVP		0.94
MPC		1.4
ClinPred		0.78	D
GERP RS		5.8
PromoterAI		0.032	Neutral
gMVP		0.83
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
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: rs747083495; hg19: chr12-2224390;