rs10848632

Variant names:

• chr12-2206827-C-T
• rs10848632
• NM_000719.7:c.477+86397C>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.477+86397C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 152,134 control chromosomes in the GnomAD database, including 9,328 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 0.34 (9328 hom., cov: 33)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.368
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.477+86397C>T		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.477+86397C>T		intron	N/A	NP_001161095.1
	CACNA1C	NM_199460.4		c.477+86397C>T		intron	N/A	NP_955630.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.477+86397C>T		intron	N/A	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.477+86397C>T		intron	N/A	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.567+86397C>T		intron	N/A	ENSP00000507184.1

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51819 AN: 152016 Hom.: 9324 Cov.: 33

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.332

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

GnomAD4 genome AF: 0.341 AC: 51849 AN: 152134 Hom.: 9328 Cov.: 33 AF XY: 0.341 AC XY: 25357 AN XY: 74366

African (AFR) AF: 0.247 AC: 10259 AN: 41492

American (AMR) AF: 0.358 AC: 5470 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 1382 AN: 3472

East Asian (EAS) AF: 0.350 AC: 1812 AN: 5180

South Asian (SAS) AF: 0.388 AC: 1871 AN: 4828

European-Finnish (FIN) AF: 0.367 AC: 3878 AN: 10560

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26062 AN: 67998

Other (OTH) AF: 0.328 AC: 690 AN: 2104

Alfa AF: 0.258 Hom.: 928

Bravo AF: 0.333

Asia WGS AF: 0.328 AC: 1139 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.8
DANN	Benign	0.70
PhyloP100		0.37
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: rs10848632; hg19: chr12-2315993;