12-2053382-G-A

Position:

• chr12-2053382-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_000719.7(CACNA1C):​c.-181G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,380,338 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: CACNA1C NM_000719.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.06

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=-0.34).
• BP6: Variant 12-2053382-G-A is Benign according to our data. Variant chr12-2053382-G-A is described in ClinVar as [Benign]. Clinvar id is 1270880.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00211 (322/152254) while in subpopulation AMR AF= 0.00294 (45/15310). AF 95% confidence interval is 0.00248. There are 1 homozygotes in gnomad4. There are 157 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 322 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.-181G>A		5_prime_UTR_variant	1/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.-181G>A		5_prime_UTR_variant	1/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.-181G>A		5_prime_UTR_variant	1/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.-181G>A		5_prime_UTR_variant	1/47	1	NM_000719.7

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 152136 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00236 AC: 2893 AN: 1228084 Hom.: 9 Cov.: 32 AF XY: 0.00232 AC XY: 1380 AN XY: 594714

Gnomad4 AFR exome AF: 0.000305

Gnomad4 AMR exome AF: 0.00357

Gnomad4 ASJ exome AF: 0.00861

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000135

Gnomad4 FIN exome AF: 0.000400

Gnomad4 NFE exome AF: 0.00250

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152254 Hom.: 1 Cov.: 31 AF XY: 0.00211 AC XY: 157 AN XY: 74442

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00281

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00250 Hom.: 0

Bravo AF: 0.00235

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.97

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs112412740; hg19: chr12-2162548; COSMIC: COSV59760930; COSMIC: COSV59760930;