chr12-2682634-T-G

Variant names:

• chr12-2682634-T-G
• rs371831239
• NM_000719.7:c.5529T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000719.7(CACNA1C):​c.5529T>G​(p.His1843Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1843Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.740
• Publications: 1 publications found

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]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07435736).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.5529T>G	p.His1843Gln	missense	Exon 43 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5529T>G	p.His1843Gln	missense	Exon 43 of 47	NP_001161095.1
	CACNA1C	NM_199460.4		c.5778T>G	p.His1926Gln	missense	Exon 46 of 50	NP_955630.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.5529T>G	p.His1843Gln	missense	Exon 43 of 47	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5529T>G	p.His1843Gln	missense	Exon 43 of 47	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.5868T>G	p.His1956Gln	missense	Exon 46 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247298 AF XY: 0.00000745

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Aug 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs371831239, ExAC 0.002%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This sequence change replaces histidine with glutamine at codon 1843 of the CACNA1C protein (p.His1843Gln). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and glutamine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
CardioboostArm	Benign	0.0000047
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.21
DANN	Benign	0.59
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.078	N
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.074	T
MetaSVM	Uncertain	-0.10	T
PhyloP100		-0.74
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.21
Sift	Benign	0.14	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.43
MPC		0.19
ClinPred		0.073	T
GERP RS		-5.5
gMVP		0.25
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs371831239; hg19: chr12-2791800;