12-2585860-A-T

Variant names:

• chr12-2585860-A-T
• rs773015884
• NM_000719.7:c.2486A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000719.7(CACNA1C):​c.2486A>T​(p.Asn829Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. N829S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.56
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a region_of_interest Interaction with STAC2 (size 47) in uniprot entity CAC1C_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_000719.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26235133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2576A>T	p.Asn859Ile	missense_variant	Exon 18 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2651A>T	p.Asn884Ile	missense_variant	Exon 19 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2576A>T	p.Asn859Ile	missense_variant	Exon 18 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2576A>T	p.Asn859Ile	missense_variant	Exon 18 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2576A>T	p.Asn859Ile	missense_variant	Exon 18 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2576A>T	p.Asn859Ile	missense_variant	Exon 18 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2561A>T	p.Asn854Ile	missense_variant	Exon 19 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2561A>T	p.Asn854Ile	missense_variant	Exon 19 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2477A>T	p.Asn826Ile	missense_variant	Exon 18 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2486A>T	p.Asn829Ile	missense_variant	Exon 18 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1093A>T		non_coding_transcript_exon_variant	Exon 16 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1093A>T		3_prime_UTR_variant	Exon 16 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000412 AC: 1 AN: 242728 AF XY: 0.00000761

Gnomad AFR exome AF: 0.00

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: 0.00000908

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457028 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724286

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 84790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109664

Other (OTH) AF: 0.00 AC: 0 AN: 60222

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Aug 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 829 of the CACNA1C protein (p.Asn829Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Benign	0.00021
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.086
Eigen_PC	Benign	0.0072
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.3	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PhyloP100		5.6
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.075	T;T;D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Uncertain	0.046	D;D;D;D;D;T;D;D;D;D;D;T;D;D;T;D;T;D;D;D;D;D;D
Polyphen		0.14, 0.19, 0.12, 0.035, 0.11, 0.20, 0.0010, 0.12, 0.51, 0.44	.;B;B;B;B;B;B;B;B;B;B;B;B;B;P;B;.;B;B;.;B;.;B
Vest4		0.42
MutPred		0.29		.;Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);Gain of catalytic residue at L826 (P = 5e-04);
MVP		0.71
MPC		1.4
ClinPred		0.39	T
GERP RS		3.4
gMVP		0.37
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs773015884; hg19: chr12-2695026;