12-2567722-C-T

Position:

• chr12-2567722-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP2 BS2

The NM_000719.7(CACNA1C):​c.1823C>T​(p.Thr608Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.74

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a topological_domain Extracellular (size 8) in uniprot entity CAC1C_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• 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.
• BS2: High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1823C>T	p.Thr608Ile	missense_variant	13/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1823C>T	p.Thr608Ile	missense_variant	13/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1823C>T	p.Thr608Ile	missense_variant	13/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1823C>T	p.Thr608Ile	missense_variant	13/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1913C>T	p.Thr638Ile	missense_variant	13/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1823C>T	p.Thr608Ile	missense_variant	13/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1823C>T	p.Thr608Ile	missense_variant	13/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1988C>T	p.Thr663Ile	missense_variant	14/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1823C>T	p.Thr608Ile	missense_variant	13/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1823C>T	p.Thr608Ile	missense_variant	13/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1823C>T	p.Thr608Ile	missense_variant	13/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1823C>T	p.Thr608Ile	missense_variant	13/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1913C>T	p.Thr638Ile	missense_variant	13/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1913C>T	p.Thr638Ile	missense_variant	13/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1913C>T	p.Thr638Ile	missense_variant	13/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1913C>T	p.Thr638Ile	missense_variant	13/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1823C>T	p.Thr608Ile	missense_variant	13/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1898C>T	p.Thr633Ile	missense_variant	14/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1823C>T	p.Thr608Ile	missense_variant	13/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1823C>T	p.Thr608Ile	missense_variant	13/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1823C>T	p.Thr608Ile	missense_variant	13/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1823C>T	p.Thr608Ile	missense_variant	13/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1823C>T	p.Thr608Ile	missense_variant	13/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1898C>T	p.Thr633Ile	missense_variant	14/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1823C>T	p.Thr608Ile	missense_variant	13/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1823C>T	p.Thr608Ile	missense_variant	13/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1823C>T	p.Thr608Ile	missense_variant	13/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1823C>T	p.Thr608Ile	missense_variant	13/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1823C>T	p.Thr608Ile	missense_variant	13/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1823C>T	p.Thr608Ile	missense_variant	13/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1823C>T	p.Thr608Ile	missense_variant	13/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1823C>T	p.Thr608Ile	missense_variant	13/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1814C>T	p.Thr605Ile	missense_variant	13/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1823C>T	p.Thr608Ile	missense_variant	13/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*430C>T		non_coding_transcript_exon_variant	11/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*430C>T		3_prime_UTR_variant	11/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249064 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135062

Gnomad AFR exome AF: 0.00

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461492 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727034

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000261

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000555 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 27, 2019

Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar (ClinVar Variant ID# 190645; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 11, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function. ClinVar contains an entry for this variant (Variation ID: 190645). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This variant is present in population databases (rs757507674, gnomAD 0.002%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 608 of the CACNA1C protein (p.Thr608Ile). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2022

The p.T608I variant (also known as c.1823C>T), located in coding exon 13 of the CACNA1C gene, results from a C to T substitution at nucleotide position 1823. The threonine at codon 608 is replaced by isoleucine, an amino acid with similar properties. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a cardiac disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, the association of this alteration with CACNA1C-related neurodevelopmental disorder is unknown; however, the association of this alteration with CACNA1C-related long QT syndrome or Timothy syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	0.050	.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.99	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	0.60
Sift	Benign	0.51	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	0.76	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 1.0, 0.056, 0.57, 0.048, 0.19, 1.0	.;D;D;B;P;B;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.75
MutPred		0.55		.;Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);Gain of catalytic residue at L605 (P = 0);
MVP		0.97
MPC		1.2
ClinPred		0.32	T
GERP RS		5.3
gMVP		0.92

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: rs757507674; hg19: chr12-2676888;