12-2685771-C-T

Variant names:

• chr12-2685771-C-T
• rs201777030
• NM_000719.7:c.5609C>T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BP6_Very_Strong

The NM_000719.7(CACNA1C):​c.5609C>T​(p.Thr1870Met) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.01

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-AS1 (HGNC:):

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -11 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=0.0057109594).
• BP6: Variant 12-2685771-C-T is Benign according to our data. Variant chr12-2685771-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 191567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2685771-C-T is described in Lovd as [Benign]. Variant chr12-2685771-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5948C>T	p.Thr1983Met	missense_variant	Exon 47 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5822C>T	p.Thr1941Met	missense_variant	Exon 45 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5789C>T	p.Thr1930Met	missense_variant	Exon 44 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5774C>T	p.Thr1925Met	missense_variant	Exon 45 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5753C>T	p.Thr1918Met	missense_variant	Exon 46 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5732C>T	p.Thr1911Met	missense_variant	Exon 44 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5714C>T	p.Thr1905Met	missense_variant	Exon 45 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5714C>T	p.Thr1905Met	missense_variant	Exon 45 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5699C>T	p.Thr1900Met	missense_variant	Exon 44 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5699C>T	p.Thr1900Met	missense_variant	Exon 44 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5699C>T	p.Thr1900Met	missense_variant	Exon 44 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5699C>T	p.Thr1900Met	missense_variant	Exon 44 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5693C>T	p.Thr1898Met	missense_variant	Exon 45 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5684C>T	p.Thr1895Met	missense_variant	Exon 45 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5669C>T	p.Thr1890Met	missense_variant	Exon 45 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5666C>T	p.Thr1889Met	missense_variant	Exon 44 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5666C>T	p.Thr1889Met	missense_variant	Exon 44 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5666C>T	p.Thr1889Met	missense_variant	Exon 44 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5660C>T	p.Thr1887Met	missense_variant	Exon 44 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5651C>T	p.Thr1884Met	missense_variant	Exon 44 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5633C>T	p.Thr1878Met	missense_variant	Exon 43 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5633C>T	p.Thr1878Met	missense_variant	Exon 43 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5627C>T	p.Thr1876Met	missense_variant	Exon 43 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5609C>T	p.Thr1870Met	missense_variant	Exon 44 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5600C>T	p.Thr1867Met	missense_variant	Exon 44 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5576C>T	p.Thr1859Met	missense_variant	Exon 43 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 145 AN: 141892 Hom.: 1 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000696

Gnomad ASJ AF: 0.000309

Gnomad EAS AF: 0.00187

Gnomad SAS AF: 0.00153

Gnomad FIN AF: 0.00209

Gnomad MID AF: 0.00360

Gnomad NFE AF: 0.000863

Gnomad OTH AF: 0.000526

GnomAD3 exomes AF: 0.00102 AC: 252 AN: 246240 Hom.: 0 AF XY: 0.000942 AC XY: 126 AN XY: 133800

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000676

Gnomad SAS exome AF: 0.00112

Gnomad FIN exome AF: 0.00697

Gnomad NFE exome AF: 0.000394

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000658 AC: 946 AN: 1437826 Hom.: 1 Cov.: 31 AF XY: 0.000654 AC XY: 468 AN XY: 715836

Gnomad4 AFR exome AF: 0.000182

Gnomad4 AMR exome AF: 0.000384

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000738

Gnomad4 SAS exome AF: 0.000902

Gnomad4 FIN exome AF: 0.00517

Gnomad4 NFE exome AF: 0.000467

Gnomad4 OTH exome AF: 0.000606

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00102 AC: 145 AN: 142000 Hom.: 1 Cov.: 32 AF XY: 0.00103 AC XY: 71 AN XY: 69258

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.000695

Gnomad4 ASJ AF: 0.000309

Gnomad4 EAS AF: 0.00188

Gnomad4 SAS AF: 0.00153

Gnomad4 FIN AF: 0.00209

Gnomad4 NFE AF: 0.000863

Gnomad4 OTH AF: 0.000522

Alfa AF: 0.0938 Hom.: 3188

ExAC AF: 0.00352 AC: 426

EpiCase AF: 0.000439

EpiControl AF: 0.000357

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

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: 30403697, 27920829) -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 26, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.5609C>T (p.Thr1870Met) in CACNA1C gene is a missense change that involves a highly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant of interest is located outside of any known functional domain, although the functional impact of this missense change is yet to be studied. The variant is present in the large control population dataset of ExAC at a frequency 0.003 (359/119184 chrs tested, including 1 homozygote), which exceeds the maximal expected frequency of a pathogenic allele (0.00001) in this gene. The variant has been reported in multiple affected individuals as well as in numerous unaffected controls. Lastly, it has been reported as Benign by several reputable databases/clinical laboratories. Taken together, the variant was classified as Benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:3

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Feb 15, 2016

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	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0057	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.15
Sift	Benign	0.10	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		0.99, 0.32, 0.97, 0.64, 0.99, 0.87, 0.48, 0.99, 0.78, 0.92, 0.98, 0.99, 0.93	.;D;B;D;P;D;P;P;P;D;P;P;D;P;P;.;P;D;.;.;.;P;.
Vest4		0.49
MVP		0.52
MPC		0.33
ClinPred		0.029	T
GERP RS		4.3
gMVP		0.39

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: rs201777030; hg19: chr12-2794937; COSMIC: COSV59698677; COSMIC: COSV59698677;