rs112532048

Variant names:

• chr12-2585485-C-T
• rs112532048
• NM_000719.7:c.2449C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000719.7(CACNA1C):​c.2449C>T​(p.Pro817Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00409 in 1,561,540 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (12 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.63

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 -19 ACMG points.

• 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=0.006192893).
• BP6: Variant 12-2585485-C-T is Benign according to our data. Variant chr12-2585485-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2585485-C-T is described in Lovd as [Benign]. Variant chr12-2585485-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00264 (402/152310) while in subpopulation NFE AF= 0.00456 (310/68028). AF 95% confidence interval is 0.00414. There are 2 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 402 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2539C>T	p.Pro847Ser	missense_variant	Exon 17 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2614C>T	p.Pro872Ser	missense_variant	Exon 18 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2539C>T	p.Pro847Ser	missense_variant	Exon 17 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2539C>T	p.Pro847Ser	missense_variant	Exon 17 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2539C>T	p.Pro847Ser	missense_variant	Exon 17 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2539C>T	p.Pro847Ser	missense_variant	Exon 17 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2524C>T	p.Pro842Ser	missense_variant	Exon 18 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2524C>T	p.Pro842Ser	missense_variant	Exon 18 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2440C>T	p.Pro814Ser	missense_variant	Exon 17 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2449C>T	p.Pro817Ser	missense_variant	Exon 17 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1056C>T		non_coding_transcript_exon_variant	Exon 15 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1056C>T		3_prime_UTR_variant	Exon 15 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 402 AN: 152192 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00456

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00233 AC: 395 AN: 169644 Hom.: 0 AF XY: 0.00217 AC XY: 196 AN XY: 90492

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000349

Gnomad FIN exome AF: 0.000293

Gnomad NFE exome AF: 0.00438

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00424 AC: 5978 AN: 1409230 Hom.: 12 Cov.: 31 AF XY: 0.00410 AC XY: 2855 AN XY: 696258

Gnomad4 AFR exome AF: 0.000740

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00399

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000276

Gnomad4 FIN exome AF: 0.000520

Gnomad4 NFE exome AF: 0.00512

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome AF: 0.00264 AC: 402 AN: 152310 Hom.: 2 Cov.: 33 AF XY: 0.00216 AC XY: 161 AN XY: 74484

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00456

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00420 Hom.: 3

Bravo AF: 0.00261

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000738 AC: 3

ESP6500EA AF: 0.00468 AC: 39

ExAC AF: 0.00194 AC: 229

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24439875) -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: PP2, BS1 -

Jul 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Jun 22, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CACNA1C-related disorder Benign:1

May 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Timothy syndrome Benign:1

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as likely benign. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Long QT syndrome 8 (MIM #618447), and Timothy syndrome (MIM#601005). Missense variants result in loss of channel inactivation, and increased current (OMIM, PMID: 25260352). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of Timothy syndrome and LQTS. Variant is present in gnomAD (503 heterozygotes (v2), 1 homozygote (v3)). (SB) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0805 - This variant has strong previous evidence of being benign in unrelated individuals. This variant has one likely benign and five benign entries in ClinVar. (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Long QT syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Benign:1

Feb 07, 2018

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 27, 2017

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	-0.23	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0062	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	0.59	D
MutationAssessor	Benign	0.92	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.7	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	0.34
Sift	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
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.78, 0.29, 0.0010, 0.029, 0.18, 0.84, 0.75, 1.0, 0.91, 0.78	.;P;B;B;B;B;P;P;P;B;P;P;P;P;D;P;.;P;P;.;P;.;P
Vest4		0.38
MVP		0.72
MPC		1.9
ClinPred		0.020	T
GERP RS		6.0
gMVP		0.37

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: rs112532048; hg19: chr12-2694651; COSMIC: COSV99046735;