rs55792866

chr12-2120310-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000719.7(CACNA1C):c.372-15G>A variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.0251 in 1,264,380 control chromosomes in the GnomAD database, including 539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (88 hom., cov: 33)
  • Exomes 𝑓: 0.025 (451 hom.)
• Consequence: CACNA1C NM_000719.7 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.47

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-2120310-G-A is Benign according to our data. Variant chr12-2120310-G-A is described in ClinVar as [Benign]. Clinvar id is 35768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2120310-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0294 (4469/152234) while in subpopulation AFR AF= 0.0487 (2024/41538). AF 95% confidence interval is 0.047. There are 88 homozygotes in gnomad4. There are 2154 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 4461 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.372-15G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000399655.6
CACNA1C	NM_001167623.2	c.372-15G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.372-15G>A		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.372-15G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000719.7

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 4461 AN: 152116 Hom.: 87 Cov.: 33

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0377

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0235

GnomAD3 exomes AF: 0.0234 AC: 5833 AN: 248948 Hom.: 99 AF XY: 0.0245 AC XY: 3306 AN XY: 135010

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.0000555

Gnomad SAS exome AF: 0.0371

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.0245 AC: 27248 AN: 1112146 Hom.: 451 Cov.: 16 AF XY: 0.0254 AC XY: 14500 AN XY: 570822

Gnomad4 AFR exome AF: 0.0484

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.0227

Gnomad4 EAS exome AF: 0.000184

Gnomad4 SAS exome AF: 0.0393

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.0250

Gnomad4 OTH exome AF: 0.0235

GnomAD4 genome AF: 0.0294 AC: 4469 AN: 152234 Hom.: 88 Cov.: 33 AF XY: 0.0289 AC XY: 2154 AN XY: 74438

Gnomad4 AFR AF: 0.0487

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0375

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.0258

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0255 Hom.: 16

Bravo AF: 0.0294

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 11, 2019	Variant summary: CACNA1C c.372-15G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.023 in 248948 control chromosomes in the gnomAD database, including 99 homozygotes. The observed variant frequency is approximately 2343-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.372-15G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 01, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	16
Dann	Benign	0.67

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: rs55792866; hg19: chr12-2229476;