rs2238043

Variant names:

• chr12-2166497-G-A
• rs2238043
• NM_000719.7:c.477+46067G>A

Variant summary

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

The NM_000719.7(CACNA1C):​c.477+46067G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 151,988 control chromosomes in the GnomAD database, including 17,865 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 0.48 (17865 hom., cov: 32)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.132
• Publications: 6 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

LOC107984131 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.575 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.477+46067G>A		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.477+46067G>A		intron	N/A	NP_001161095.1
	CACNA1C	NM_199460.4		c.477+46067G>A		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.477+46067G>A		intron	N/A	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.477+46067G>A		intron	N/A	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.567+46067G>A		intron	N/A	ENSP00000507184.1

Frequencies

GnomAD3 genomes AF: 0.480 AC: 72859 AN: 151870 Hom.: 17834 Cov.: 32

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.480 AC: 72950 AN: 151988 Hom.: 17865 Cov.: 32 AF XY: 0.484 AC XY: 35960 AN XY: 74276

African (AFR) AF: 0.555 AC: 23001 AN: 41430

American (AMR) AF: 0.443 AC: 6764 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1308 AN: 3466

East Asian (EAS) AF: 0.576 AC: 2979 AN: 5174

South Asian (SAS) AF: 0.593 AC: 2856 AN: 4814

European-Finnish (FIN) AF: 0.479 AC: 5058 AN: 10564

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29497 AN: 67956

Other (OTH) AF: 0.448 AC: 943 AN: 2106

Alfa AF: 0.458 Hom.: 12347

Bravo AF: 0.475

Asia WGS AF: 0.583 AC: 2023 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.7
DANN	Benign	0.45
PhyloP100		0.13
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: rs2238043; hg19: chr12-2275663;