chr12-2236129-G-A

Position:

• chr12-2236129-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000719.7(CACNA1C):​c.477+115699G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 152,038 control chromosomes in the GnomAD database, including 10,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain risk allele (no stars).

• Frequency: Genomes: 𝑓 0.35 (10258 hom., cov: 32)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Uncertain risk allele no assertion criteria provided O:1
• Conservation: PhyloP100: 0.248

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.477+115699G>A		intron_variant		ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.477+115699G>A		intron_variant		ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.477+115699G>A		intron_variant		5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.477+115699G>A		intron_variant		1	NM_000719.7	ENSP00000382563

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53833 AN: 151920 Hom.: 10263 Cov.: 32

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.0516

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.328

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

GnomAD4 genome AF: 0.354 AC: 53869 AN: 152038 Hom.: 10258 Cov.: 32 AF XY: 0.349 AC XY: 25918 AN XY: 74314

Gnomad4 AFR AF: 0.479

Gnomad4 AMR AF: 0.286

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.0514

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.318

Gnomad4 NFE AF: 0.335

Gnomad4 OTH AF: 0.323

Alfa AF: 0.320 Hom.: 11497

Bravo AF: 0.353

Asia WGS AF: 0.150 AC: 527 AN: 3478

ClinVar

Significance: Uncertain risk allele

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Post-traumatic stress disorder Other:1

Uncertain risk allele, no assertion criteria provided

research

Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.1
DANN	Benign	0.63

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: rs1006737; hg19: chr12-2345295;