rs34621387

Variant names:

• chr12-2419238-A-G
• rs34621387
• NM_000719.7:c.478-29738A>G

Variant summary

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

The NM_000719.7(CACNA1C):​c.478-29738A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 151,998 control chromosomes in the GnomAD database, including 13,818 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 0.42 (13818 hom., cov: 32)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.79
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.07).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.478-29738A>G		intron_variant	Intron 3 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.478-29738A>G		intron_variant	Intron 3 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.478-29738A>G		intron_variant	Intron 3 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.478-29738A>G		intron_variant	Intron 3 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.568-29738A>G		intron_variant	Intron 3 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.478-29738A>G		intron_variant	Intron 3 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.478-29738A>G		intron_variant	Intron 3 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.568-29738A>G		intron_variant	Intron 3 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.478-29738A>G		intron_variant	Intron 3 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.478-29738A>G		intron_variant	Intron 3 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.478-29738A>G		intron_variant	Intron 3 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.478-29738A>G		intron_variant	Intron 3 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.568-29738A>G		intron_variant	Intron 3 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.568-29738A>G		intron_variant	Intron 3 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.568-29738A>G		intron_variant	Intron 3 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.568-29738A>G		intron_variant	Intron 3 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.478-29738A>G		intron_variant	Intron 3 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.478-29738A>G		intron_variant	Intron 3 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.478-29738A>G		intron_variant	Intron 3 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.478-29738A>G		intron_variant	Intron 3 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.478-29738A>G		intron_variant	Intron 3 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.478-29738A>G		intron_variant	Intron 3 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.478-29738A>G		intron_variant	Intron 3 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.478-29738A>G		intron_variant	Intron 3 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.478-29738A>G		intron_variant	Intron 3 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.478-29738A>G		intron_variant	Intron 3 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.478-29738A>G		intron_variant	Intron 3 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.478-29738A>G		intron_variant	Intron 3 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.478-29738A>G		intron_variant	Intron 3 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.478-29738A>G		intron_variant	Intron 3 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.478-29738A>G		intron_variant	Intron 3 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.478-29738A>G		intron_variant	Intron 3 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.478-29738A>G		intron_variant	Intron 3 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.478-29738A>G		intron_variant	Intron 3 of 45			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.427-29738A>G		intron_variant	Intron 2 of 5			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.478-29738A>G		intron_variant	Intron 3 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64301 AN: 151880 Hom.: 13802 Cov.: 32

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.420

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

GnomAD4 genome AF: 0.423 AC: 64351 AN: 151998 Hom.: 13818 Cov.: 32 AF XY: 0.421 AC XY: 31249 AN XY: 74308

African (AFR) AF: 0.420 AC: 17387 AN: 41442

American (AMR) AF: 0.394 AC: 6030 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1779 AN: 3472

East Asian (EAS) AF: 0.243 AC: 1250 AN: 5152

South Asian (SAS) AF: 0.333 AC: 1605 AN: 4816

European-Finnish (FIN) AF: 0.446 AC: 4713 AN: 10566

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.443 AC: 30125 AN: 67948

Other (OTH) AF: 0.425 AC: 894 AN: 2104

Alfa AF: 0.429 Hom.: 1750

Bravo AF: 0.420

Asia WGS AF: 0.351 AC: 1220 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.33
DANN	Benign	0.13
PhyloP100		-1.8
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: rs34621387; hg19: chr12-2528404;