12-2688673-G-T

Variant names:

• chr12-2688673-G-T
• rs374991642
• NM_000719.7:c.6011G>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.6011G>T​(p.Gly2004Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.36

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 Likely_benign. Variant got -6 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=0.116500765).
• BP6: Variant 12-2688673-G-T is Benign according to our data. Variant chr12-2688673-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456989.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6011G>T	p.Gly2004Val	missense_variant	Exon 46 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6011G>T	p.Gly2004Val	missense_variant	Exon 46 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6011G>T	p.Gly2004Val	missense_variant	Exon 46 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6011G>T	p.Gly2004Val	missense_variant	Exon 46 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6350G>T	p.Gly2117Val	missense_variant	Exon 49 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6224G>T	p.Gly2075Val	missense_variant	Exon 47 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6191G>T	p.Gly2064Val	missense_variant	Exon 46 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6176G>T	p.Gly2059Val	missense_variant	Exon 47 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6155G>T	p.Gly2052Val	missense_variant	Exon 48 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6134G>T	p.Gly2045Val	missense_variant	Exon 46 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6116G>T	p.Gly2039Val	missense_variant	Exon 47 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6116G>T	p.Gly2039Val	missense_variant	Exon 47 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6101G>T	p.Gly2034Val	missense_variant	Exon 46 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6101G>T	p.Gly2034Val	missense_variant	Exon 46 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6101G>T	p.Gly2034Val	missense_variant	Exon 46 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6101G>T	p.Gly2034Val	missense_variant	Exon 46 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6095G>T	p.Gly2032Val	missense_variant	Exon 47 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6086G>T	p.Gly2029Val	missense_variant	Exon 47 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6071G>T	p.Gly2024Val	missense_variant	Exon 47 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6068G>T	p.Gly2023Val	missense_variant	Exon 46 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6068G>T	p.Gly2023Val	missense_variant	Exon 46 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6068G>T	p.Gly2023Val	missense_variant	Exon 46 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6062G>T	p.Gly2021Val	missense_variant	Exon 46 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6053G>T	p.Gly2018Val	missense_variant	Exon 46 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6035G>T	p.Gly2012Val	missense_variant	Exon 45 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6035G>T	p.Gly2012Val	missense_variant	Exon 45 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6029G>T	p.Gly2010Val	missense_variant	Exon 45 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6011G>T	p.Gly2004Val	missense_variant	Exon 46 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6011G>T	p.Gly2004Val	missense_variant	Exon 46 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6011G>T	p.Gly2004Val	missense_variant	Exon 46 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6011G>T	p.Gly2004Val	missense_variant	Exon 46 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6011G>T	p.Gly2004Val	missense_variant	Exon 46 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6002G>T	p.Gly2001Val	missense_variant	Exon 46 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5978G>T	p.Gly1993Val	missense_variant	Exon 45 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000771 AC: 19 AN: 246344 Hom.: 0 AF XY: 0.0000522 AC XY: 7 AN XY: 134082

Gnomad AFR exome AF: 0.0000662

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000153

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1461020 Hom.: 0 Cov.: 33 AF XY: 0.000102 AC XY: 74 AN XY: 726854

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74486

Gnomad4 AFR AF: 0.0000241

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: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.000108 AC: 13

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Aug 17, 2020

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CACNA1C c.6011G>T (p.Gly2004Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 246344 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Timothy Syndrome phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.6011G>T in individuals affected with Timothy Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign. -

Long QT syndrome Benign:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jan 07, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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	-0.20	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	11
DANN	Benign	0.65
DEOGEN2	Benign	0.021	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.12	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	-0.33	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.30
Sift	Benign	0.041	D;T;D;D;D;D;D;D;D;D;D;D;T;D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.20	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	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.21
MVP		0.37
MPC		0.24
ClinPred		0.050	T
GERP RS		-0.69
gMVP		0.29

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: rs374991642; hg19: chr12-2797839;