12-2688658-C-T

Position:

• chr12-2688658-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_000719.7(CACNA1C):​c.5996C>T​(p.Thr1999Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 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 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.348

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.06522894).
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5996C>T	p.Thr1999Ile	missense_variant	46/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5996C>T	p.Thr1999Ile	missense_variant	46/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5996C>T	p.Thr1999Ile	missense_variant	46/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5996C>T	p.Thr1999Ile	missense_variant	46/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6335C>T	p.Thr2112Ile	missense_variant	49/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6209C>T	p.Thr2070Ile	missense_variant	47/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6176C>T	p.Thr2059Ile	missense_variant	46/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6161C>T	p.Thr2054Ile	missense_variant	47/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6140C>T	p.Thr2047Ile	missense_variant	48/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6119C>T	p.Thr2040Ile	missense_variant	46/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6101C>T	p.Thr2034Ile	missense_variant	47/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6101C>T	p.Thr2034Ile	missense_variant	47/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6086C>T	p.Thr2029Ile	missense_variant	46/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6086C>T	p.Thr2029Ile	missense_variant	46/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6086C>T	p.Thr2029Ile	missense_variant	46/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6086C>T	p.Thr2029Ile	missense_variant	46/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6080C>T	p.Thr2027Ile	missense_variant	47/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6071C>T	p.Thr2024Ile	missense_variant	47/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6056C>T	p.Thr2019Ile	missense_variant	47/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6053C>T	p.Thr2018Ile	missense_variant	46/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6053C>T	p.Thr2018Ile	missense_variant	46/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6053C>T	p.Thr2018Ile	missense_variant	46/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6047C>T	p.Thr2016Ile	missense_variant	46/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6038C>T	p.Thr2013Ile	missense_variant	46/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6020C>T	p.Thr2007Ile	missense_variant	45/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6020C>T	p.Thr2007Ile	missense_variant	45/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6014C>T	p.Thr2005Ile	missense_variant	45/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5996C>T	p.Thr1999Ile	missense_variant	46/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5996C>T	p.Thr1999Ile	missense_variant	46/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5996C>T	p.Thr1999Ile	missense_variant	46/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5996C>T	p.Thr1999Ile	missense_variant	46/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5996C>T	p.Thr1999Ile	missense_variant	46/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5987C>T	p.Thr1996Ile	missense_variant	46/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5963C>T	p.Thr1988Ile	missense_variant	45/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000566 AC: 14 AN: 247404 Hom.: 0 AF XY: 0.0000817 AC XY: 11 AN XY: 134608

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000894

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461304 Hom.: 0 Cov.: 33 AF XY: 0.0000330 AC XY: 24 AN XY: 726976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74482

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long qt syndrome 8 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Feb 15, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.6245C>T (p.Thr2082Ile) in CACNA1C gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Thr2082Ile variant is reported with the allele frequency (0.005%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Thr at position 2082 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Thr2082Ile in CACNA1C is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS) -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 29, 2021

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2024

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	-0.35	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.4
DANN	Benign	0.97
DEOGEN2	Benign	0.023	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.032	N
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.065	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	-0.99	T
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.065
Sift	Benign	0.080	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.14, 0.0010, 0.0090, 0.30, 0.12, 0.068, 0.056, 0.12	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.35
MVP		0.15
MPC		0.21
ClinPred		0.027	T
GERP RS		2.2
gMVP		0.36

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: rs532551057; hg19: chr12-2797824;