NM_000719.7:c.3828+8453A>G

Variant names:

• chr12-2620466-A-G
• rs216013
• NM_000719.7:c.3828+8453A>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.3828+8453A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 152,170 control chromosomes in the GnomAD database, including 2,624 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 0.18 (2624 hom., cov: 33)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 19 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3828+8453A>G		intron_variant	Intron 29 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3828+8453A>G		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.3828+8453A>G		intron_variant	Intron 29 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3828+8453A>G		intron_variant	Intron 29 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3978+8453A>G		intron_variant	Intron 30 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3828+8453A>G		intron_variant	Intron 29 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3828+8453A>G		intron_variant	Intron 29 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3993+8453A>G		intron_variant	Intron 30 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3888+8453A>G		intron_variant	Intron 30 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3828+8453A>G		intron_variant	Intron 29 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3828+8453A>G		intron_variant	Intron 29 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3828+8453A>G		intron_variant	Intron 29 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3918+8453A>G		intron_variant	Intron 29 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3918+8453A>G		intron_variant	Intron 29 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3918+8453A>G		intron_variant	Intron 29 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3918+8453A>G		intron_variant	Intron 29 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3828+8453A>G		intron_variant	Intron 29 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3903+8453A>G		intron_variant	Intron 30 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3888+8453A>G		intron_variant	Intron 30 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3828+8453A>G		intron_variant	Intron 29 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3828+8453A>G		intron_variant	Intron 29 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3828+8453A>G		intron_variant	Intron 29 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3828+8453A>G		intron_variant	Intron 29 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3903+8453A>G		intron_variant	Intron 30 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3828+8453A>G		intron_variant	Intron 29 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3828+8453A>G		intron_variant	Intron 29 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3828+8453A>G		intron_variant	Intron 29 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3828+8453A>G		intron_variant	Intron 29 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3828+8453A>G		intron_variant	Intron 29 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3828+8453A>G		intron_variant	Intron 29 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3828+8453A>G		intron_variant	Intron 29 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3828+8453A>G		intron_variant	Intron 29 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3819+8453A>G		intron_variant	Intron 29 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3828+8453A>G		intron_variant	Intron 29 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27197 AN: 152052 Hom.: 2622 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.282

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.0857

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.194

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

GnomAD4 genome AF: 0.179 AC: 27227 AN: 152170 Hom.: 2624 Cov.: 33 AF XY: 0.177 AC XY: 13206 AN XY: 74418

African (AFR) AF: 0.221 AC: 9185 AN: 41508

American (AMR) AF: 0.226 AC: 3459 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 676 AN: 3470

East Asian (EAS) AF: 0.282 AC: 1457 AN: 5170

South Asian (SAS) AF: 0.193 AC: 930 AN: 4812

European-Finnish (FIN) AF: 0.0857 AC: 909 AN: 10608

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9985 AN: 67996

Other (OTH) AF: 0.195 AC: 412 AN: 2114

Alfa AF: 0.163 Hom.: 10117

Bravo AF: 0.189

Asia WGS AF: 0.228 AC: 795 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.9
DANN	Benign	0.67
PhyloP100		1.0
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: rs216013; hg19: chr12-2729632;