12-2069594-G-C

Variant names:

• chr12-2069594-G-C
• rs4765663
• NM_000719.7:c.49+15983G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000347598.9(CACNA1C):​c.49+15983G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 152,164 control chromosomes in the GnomAD database, including 1,703 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1703 hom., cov: 32)
• Consequence: CACNA1C ENST00000347598.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.769
• Publications: 8 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]

CACNA1C Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• long QT syndrome 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
• Brugada syndrome 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000347598.9. 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.49+15983G>C		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.49+15983G>C		intron	N/A	NP_001161095.1
	CACNA1C	NM_199460.4		c.49+15983G>C		intron	N/A	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.49+15983G>C		intron	N/A	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.49+15983G>C		intron	N/A	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.140-45630G>C		intron	N/A	ENSP00000507184.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21878 AN: 152046 Hom.: 1706 Cov.: 32

Gnomad AFR AF: 0.0852

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.140

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

GnomAD4 genome AF: 0.144 AC: 21878 AN: 152164 Hom.: 1703 Cov.: 32 AF XY: 0.149 AC XY: 11105 AN XY: 74384

African (AFR) AF: 0.0851 AC: 3531 AN: 41516

American (AMR) AF: 0.123 AC: 1876 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 538 AN: 3468

East Asian (EAS) AF: 0.177 AC: 914 AN: 5174

South Asian (SAS) AF: 0.200 AC: 965 AN: 4822

European-Finnish (FIN) AF: 0.247 AC: 2609 AN: 10568

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 10992 AN: 67996

Other (OTH) AF: 0.140 AC: 296 AN: 2114

Alfa AF: 0.0856 Hom.: 114

Bravo AF: 0.131

Asia WGS AF: 0.191 AC: 666 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.44
PhyloP100		0.77
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: rs4765663; hg19: chr12-2178760;