chr12-2674806-T-C

Variant names:

• chr12-2674806-T-C
• rs2302729
• NM_000719.7:c.4828+164T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000719.7(CACNA1C):​c.4828+164T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 152,134 control chromosomes in the GnomAD database, including 40,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.71 (40573 hom., cov: 33)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.05
• Publications: 15 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-2674806-T-C is Benign according to our data. Variant chr12-2674806-T-C is described in ClinVar as Benign. ClinVar VariationId is 671811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.4828+164T>C		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.4828+164T>C		intron	N/A	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.4972+164T>C		intron	N/A	NP_955630.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.4828+164T>C		intron	N/A	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.4828+164T>C		intron	N/A	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.5062+164T>C		intron	N/A	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.711 AC: 108052 AN: 152016 Hom.: 40563 Cov.: 33

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.849

Gnomad FIN AF: 0.859

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.726

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.711 AC: 108094 AN: 152134 Hom.: 40573 Cov.: 33 AF XY: 0.714 AC XY: 53110 AN XY: 74386

African (AFR) AF: 0.450 AC: 18647 AN: 41458

American (AMR) AF: 0.741 AC: 11321 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 2915 AN: 3470

East Asian (EAS) AF: 0.624 AC: 3215 AN: 5154

South Asian (SAS) AF: 0.848 AC: 4088 AN: 4822

European-Finnish (FIN) AF: 0.859 AC: 9117 AN: 10618

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.829 AC: 56382 AN: 68012

Other (OTH) AF: 0.727 AC: 1535 AN: 2112

Alfa AF: 0.795 Hom.: 200571

Bravo AF: 0.689

Asia WGS AF: 0.724 AC: 2514 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.17
DANN	Benign	0.73
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2302729; hg19: chr12-2783972;