NM_000719.7:c.2486A>G

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1 PP2 BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.2486A>G​(p.Asn829Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,609,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.56

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a region_of_interest Interaction with STAC2 (size 47) in uniprot entity CAC1C_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08768231).
• BP6: Variant 12-2585860-A-G is Benign according to our data. Variant chr12-2585860-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 570822.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2486A>G	p.Asn829Ser	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>G	p.Asn829Ser	missense_variant	Exon 18 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2576A>G	p.Asn859Ser	missense_variant	Exon 18 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2651A>G	p.Asn884Ser	missense_variant	Exon 19 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2576A>G	p.Asn859Ser	missense_variant	Exon 18 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2576A>G	p.Asn859Ser	missense_variant	Exon 18 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2576A>G	p.Asn859Ser	missense_variant	Exon 18 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2576A>G	p.Asn859Ser	missense_variant	Exon 18 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2561A>G	p.Asn854Ser	missense_variant	Exon 19 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2561A>G	p.Asn854Ser	missense_variant	Exon 19 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2477A>G	p.Asn826Ser	missense_variant	Exon 18 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2486A>G	p.Asn829Ser	missense_variant	Exon 18 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1093A>G		non_coding_transcript_exon_variant	Exon 16 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1093A>G		3_prime_UTR_variant	Exon 16 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000288 AC: 7 AN: 242728 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131342

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000566

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000275 AC: 40 AN: 1457028 Hom.: 0 Cov.: 30 AF XY: 0.0000235 AC XY: 17 AN XY: 724286

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000901

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

Gnomad4 AFR AF: 0.0000724

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jun 11, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Sep 08, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.019	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.088	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	0.090	D
MutationAssessor	Benign	0.24	.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.0010	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;B;.;B
Vest4		0.14
MutPred		0.28		.;Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);Gain of catalytic residue at L826 (P = 0.0018);
MVP		0.59
MPC		0.85
ClinPred		0.074	T
GERP RS		3.4
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs773015884; hg19: chr12-2695026;