rs16929277

Variant names:

• chr12-2331006-C-G
• rs16929277
• NM_000719.7:c.478-117970C>G

Variant summary

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

The NM_199460.4(CACNA1C):​c.478-117970C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 152,010 control chromosomes in the GnomAD database, including 2,855 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 0.12 (2855 hom., cov: 33)
• Consequence: CACNA1C NM_199460.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.280
• Publications: 5 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199460.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.478-117970C>G		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.478-117970C>G		intron	N/A	NP_001161095.1
	CACNA1C	NM_199460.4		c.478-117970C>G		intron	N/A	NP_955630.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.478-117970C>G		intron	N/A	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.478-117970C>G		intron	N/A	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.568-117970C>G		intron	N/A	ENSP00000507184.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17950 AN: 151892 Hom.: 2837 Cov.: 33

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0786

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.0245

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0962

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

GnomAD4 genome AF: 0.119 AC: 18018 AN: 152010 Hom.: 2855 Cov.: 33 AF XY: 0.115 AC XY: 8569 AN XY: 74320

African (AFR) AF: 0.364 AC: 15083 AN: 41400

American (AMR) AF: 0.0783 AC: 1198 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3466

East Asian (EAS) AF: 0.0245 AC: 127 AN: 5178

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4806

European-Finnish (FIN) AF: 0.0146 AC: 154 AN: 10578

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0164 AC: 1116 AN: 67970

Other (OTH) AF: 0.102 AC: 216 AN: 2112

Alfa AF: 0.0773 Hom.: 218

Bravo AF: 0.136

Asia WGS AF: 0.0860 AC: 301 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.9
DANN	Benign	0.73
PhyloP100		0.28
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: rs16929277; hg19: chr12-2440172;