12-2052395-C-T

Variant names:

• chr12-2052395-C-T
• rs723672
• ENST00000682544.1:c.140-62829C>T

Variant summary

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

The ENST00000682544.1(CACNA1C):​c.140-62829C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 151,758 control chromosomes in the GnomAD database, including 25,043 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 0.55 (25043 hom., cov: 31)
• Consequence: CACNA1C ENST00000682544.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.339
• Publications: 12 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=-0.56).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	XM_017019926.3	c.217+16806C>T		intron_variant	Intron 2 of 52		XP_016875415.1
CACNA1C	XM_017019927.3	c.217+16806C>T		intron_variant	Intron 2 of 51		XP_016875416.1
CACNA1C	XM_047429513.1	c.217+16806C>T		intron_variant	Intron 2 of 51		XP_047285469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000682544.1	c.140-62829C>T		intron_variant	Intron 1 of 49			ENSP00000507184.1
CACNA1C	ENST00000683824.1	c.140-62829C>T		intron_variant	Intron 1 of 47			ENSP00000507867.1
CACNA1C	ENST00000682462.1	c.140-62829C>T		intron_variant	Intron 1 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.140-62829C>T		intron_variant	Intron 1 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.140-62829C>T		intron_variant	Intron 1 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.140-62829C>T		intron_variant	Intron 1 of 46			ENSP00000506882.1

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83446 AN: 151640 Hom.: 24991 Cov.: 31

Gnomad AFR AF: 0.788

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.733

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.525

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

GnomAD4 genome AF: 0.551 AC: 83551 AN: 151758 Hom.: 25043 Cov.: 31 AF XY: 0.552 AC XY: 40951 AN XY: 74120

African (AFR) AF: 0.788 AC: 32658 AN: 41446

American (AMR) AF: 0.465 AC: 7098 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1296 AN: 3472

East Asian (EAS) AF: 0.732 AC: 3712 AN: 5068

South Asian (SAS) AF: 0.542 AC: 2605 AN: 4808

European-Finnish (FIN) AF: 0.476 AC: 4992 AN: 10490

Middle Eastern (MID) AF: 0.517 AC: 151 AN: 292

European-Non Finnish (NFE) AF: 0.438 AC: 29710 AN: 67892

Other (OTH) AF: 0.527 AC: 1113 AN: 2110

Alfa AF: 0.499 Hom.: 10751

Bravo AF: 0.564

Asia WGS AF: 0.645 AC: 2242 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		0.34

Splicing

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

Other links and lift over

dbSNP: rs723672; hg19: chr12-2161561;