12-2632628-C-T

Variant names:

• chr12-2632628-C-T
• rs11062288
• NM_000719.7:c.3829-1669C>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.3829-1669C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 152,134 control chromosomes in the GnomAD database, including 32,057 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 0.62 (32057 hom., cov: 33)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3829-1669C>T		intron_variant	Intron 29 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3829-1001C>T		intron_variant	Intron 29 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3829-1001C>T		intron_variant	Intron 29 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3829-1669C>T		intron_variant	Intron 29 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3979-1001C>T		intron_variant	Intron 30 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3829-1001C>T		intron_variant	Intron 29 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3829-1669C>T		intron_variant	Intron 29 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3994-1001C>T		intron_variant	Intron 30 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3889-1001C>T		intron_variant	Intron 30 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3829-1669C>T		intron_variant	Intron 29 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3829-1669C>T		intron_variant	Intron 29 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3829-1001C>T		intron_variant	Intron 29 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3919-1001C>T		intron_variant	Intron 29 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3919-1669C>T		intron_variant	Intron 29 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3919-1669C>T		intron_variant	Intron 29 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3919-1001C>T		intron_variant	Intron 29 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3829-1001C>T		intron_variant	Intron 29 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3904-1669C>T		intron_variant	Intron 30 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3889-1669C>T		intron_variant	Intron 30 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3829-1669C>T		intron_variant	Intron 29 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3829-1669C>T		intron_variant	Intron 29 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3829-1001C>T		intron_variant	Intron 29 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3829-1001C>T		intron_variant	Intron 29 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3904-1001C>T		intron_variant	Intron 30 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3829-1669C>T		intron_variant	Intron 29 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3829-1669C>T		intron_variant	Intron 29 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3829-1669C>T		intron_variant	Intron 29 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3829-1001C>T		intron_variant	Intron 29 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3829-1669C>T		intron_variant	Intron 29 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3829-1669C>T		intron_variant	Intron 29 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3829-1001C>T		intron_variant	Intron 29 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3829-1001C>T		intron_variant	Intron 29 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3820-1001C>T		intron_variant	Intron 29 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3829-1669C>T		intron_variant	Intron 29 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93709 AN: 152012 Hom.: 32054 Cov.: 33

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.709

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.617

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

GnomAD4 genome AF: 0.616 AC: 93737 AN: 152134 Hom.: 32057 Cov.: 33 AF XY: 0.619 AC XY: 46028 AN XY: 74402

African (AFR) AF: 0.293 AC: 12127 AN: 41448

American (AMR) AF: 0.669 AC: 10234 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 2332 AN: 3470

East Asian (EAS) AF: 0.709 AC: 3664 AN: 5170

South Asian (SAS) AF: 0.655 AC: 3157 AN: 4820

European-Finnish (FIN) AF: 0.779 AC: 8261 AN: 10602

Middle Eastern (MID) AF: 0.538 AC: 157 AN: 292

European-Non Finnish (NFE) AF: 0.761 AC: 51767 AN: 68008

Other (OTH) AF: 0.619 AC: 1307 AN: 2112

Alfa AF: 0.704 Hom.: 72216

Bravo AF: 0.595

Asia WGS AF: 0.661 AC: 2295 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.39
DANN	Benign	0.67
PhyloP100		-1.4
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: rs11062288; hg19: chr12-2741794;