12-2492576-C-T

Variant names:

• chr12-2492576-C-T
• rs16929470
• NM_000719.7:c.917-614C>T

Variant summary

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

The NM_000719.7(CACNA1C):​c.917-614C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 152,306 control chromosomes in the GnomAD database, including 191 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 0.046 (191 hom., cov: 33)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 2 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.917-614C>T		intron_variant	Intron 6 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.917-614C>T		intron_variant	Intron 6 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.917-614C>T		intron_variant	Intron 6 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.917-614C>T		intron_variant	Intron 6 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1007-614C>T		intron_variant	Intron 6 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.917-614C>T		intron_variant	Intron 6 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.917-614C>T		intron_variant	Intron 6 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1007-614C>T		intron_variant	Intron 6 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.917-614C>T		intron_variant	Intron 6 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.917-614C>T		intron_variant	Intron 6 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.917-614C>T		intron_variant	Intron 6 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.917-614C>T		intron_variant	Intron 6 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1007-614C>T		intron_variant	Intron 6 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1007-614C>T		intron_variant	Intron 6 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1007-614C>T		intron_variant	Intron 6 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1007-614C>T		intron_variant	Intron 6 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.917-614C>T		intron_variant	Intron 6 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.917-614C>T		intron_variant	Intron 6 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.917-614C>T		intron_variant	Intron 6 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.917-614C>T		intron_variant	Intron 6 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.917-614C>T		intron_variant	Intron 6 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.917-614C>T		intron_variant	Intron 6 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.917-614C>T		intron_variant	Intron 6 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.917-614C>T		intron_variant	Intron 6 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.917-614C>T		intron_variant	Intron 6 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.917-614C>T		intron_variant	Intron 6 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.917-614C>T		intron_variant	Intron 6 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.917-614C>T		intron_variant	Intron 6 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.917-614C>T		intron_variant	Intron 6 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.917-614C>T		intron_variant	Intron 6 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.917-614C>T		intron_variant	Intron 6 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.917-614C>T		intron_variant	Intron 6 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.917-623C>T		intron_variant	Intron 6 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.917-614C>T		intron_variant	Intron 6 of 45			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.866-626C>T		intron_variant	Intron 5 of 5			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.917-614C>T		intron_variant	Intron 6 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6939 AN: 152188 Hom.: 191 Cov.: 33

Gnomad AFR AF: 0.0359

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0467

Gnomad ASJ AF: 0.0481

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0469

Gnomad OTH AF: 0.0498

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

GnomAD4 genome AF: 0.0456 AC: 6939 AN: 152306 Hom.: 191 Cov.: 33 AF XY: 0.0453 AC XY: 3372 AN XY: 74472

African (AFR) AF: 0.0359 AC: 1494 AN: 41568

American (AMR) AF: 0.0465 AC: 712 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0481 AC: 167 AN: 3472

East Asian (EAS) AF: 0.137 AC: 710 AN: 5176

South Asian (SAS) AF: 0.0685 AC: 331 AN: 4830

European-Finnish (FIN) AF: 0.0181 AC: 192 AN: 10618

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0468 AC: 3187 AN: 68026

Other (OTH) AF: 0.0492 AC: 104 AN: 2112

Alfa AF: 0.0465 Hom.: 611

Bravo AF: 0.0464

Asia WGS AF: 0.0900 AC: 312 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.25
DANN	Benign	0.73
PhyloP100		-1.2
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: rs16929470; hg19: chr12-2601742;