chr12-2006081-C-T

Variant names:

• chr12-2006081-C-T
• rs2470411
• ENST00000682544.1:c.139+34880C>T

Variant summary

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

The ENST00000682544.1(CACNA1C):​c.139+34880C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 152,174 control chromosomes in the GnomAD database, including 22,931 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 0.54 (22931 hom., cov: 33)
• Consequence: CACNA1C ENST00000682544.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.59
• Publications: 1 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

ENSG00000203593 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	XM_017019926.3	c.140-29431C>T		intron_variant	Intron 1 of 52		XP_016875415.1
CACNA1C	XM_017019927.3	c.140-29431C>T		intron_variant	Intron 1 of 51		XP_016875416.1
CACNA1C	XM_047429513.1	c.140-29431C>T		intron_variant	Intron 1 of 51		XP_047285469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000682544.1	c.139+34880C>T		intron_variant	Intron 1 of 49			ENSP00000507184.1
CACNA1C	ENST00000683824.1	c.139+34880C>T		intron_variant	Intron 1 of 47			ENSP00000507867.1
CACNA1C	ENST00000682462.1	c.139+34880C>T		intron_variant	Intron 1 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.139+34880C>T		intron_variant	Intron 1 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.139+34880C>T		intron_variant	Intron 1 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.139+34880C>T		intron_variant	Intron 1 of 46			ENSP00000506882.1

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82633 AN: 152056 Hom.: 22916 Cov.: 33

Gnomad AFR AF: 0.652

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.527

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.553

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

GnomAD4 genome AF: 0.543 AC: 82695 AN: 152174 Hom.: 22931 Cov.: 33 AF XY: 0.541 AC XY: 40231 AN XY: 74386

African (AFR) AF: 0.651 AC: 27056 AN: 41538

American (AMR) AF: 0.517 AC: 7913 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1712 AN: 3470

East Asian (EAS) AF: 0.527 AC: 2729 AN: 5176

South Asian (SAS) AF: 0.428 AC: 2062 AN: 4814

European-Finnish (FIN) AF: 0.499 AC: 5278 AN: 10580

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.504 AC: 34250 AN: 67986

Other (OTH) AF: 0.554 AC: 1168 AN: 2110

Alfa AF: 0.527 Hom.: 4417

Bravo AF: 0.549

Asia WGS AF: 0.488 AC: 1699 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.87
DANN	Benign	0.82
PhyloP100		-2.6

Splicing

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

Other links and lift over

dbSNP: rs2470411; hg19: chr12-2115247;