rs773015884

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-2585860-A-G
• chr12-2585860-A-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N829I) has been classified as Uncertain significance.

• 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
• 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: Likely_benign. The variant received -5 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
• 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 submission is: [Conflicting_classifications_of_pathogenicity].
• 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

GnomAD2 exomes AF: 0.0000288 AC: 7 AN: 242728 AF XY: 0.0000152

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 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

African (AFR) AF: 0.0000599 AC: 2 AN: 33362

American (AMR) AF: 0.0000901 AC: 4 AN: 44410

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

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39592

South Asian (SAS) AF: 0.0000118 AC: 1 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: 0.0000243 AC: 27 AN: 1109664

Other (OTH) AF: 0.0000498 AC: 3 AN: 60222

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

African (AFR) AF: 0.0000724 AC: 3 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

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
CardioboostArm	Benign	0.000030
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;.;.;.
PhyloP100		5.6
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
Mutation Taster		=84/16	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;