rs2238092

Variant names:

• chr12-2614100-G-A
• rs2238092
• NM_000719.7:c.3828+2087G>A

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+2087G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 152,054 control chromosomes in the GnomAD database, including 33,668 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 0.64 (33662 hom., cov: 31)
  • Exomes 𝑓: 0.80 (6 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.54
• Publications: 4 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• 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: ClinGen, Orphanet
• 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: ClinGen, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.766 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.3828+2087G>A		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.3828+2087G>A		intron	N/A	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.3888+2087G>A		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.3828+2087G>A		intron	N/A	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.3828+2087G>A		intron	N/A	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.3978+2087G>A		intron	N/A	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.641 AC: 97396 AN: 151914 Hom.: 33654 Cov.: 31

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.654

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.772

Gnomad OTH AF: 0.644

GnomAD4 exome AF: 0.800 AC: 16 AN: 20 Hom.: 6 Cov.: 0 AF XY: 0.800 AC XY: 8 AN XY: 10

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.778 AC: 14 AN: 18

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000316713), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.641 AC: 97435 AN: 152034 Hom.: 33662 Cov.: 31 AF XY: 0.642 AC XY: 47679 AN XY: 74320

African (AFR) AF: 0.365 AC: 15109 AN: 41418

American (AMR) AF: 0.679 AC: 10370 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2448 AN: 3466

East Asian (EAS) AF: 0.654 AC: 3379 AN: 5168

South Asian (SAS) AF: 0.689 AC: 3319 AN: 4814

European-Finnish (FIN) AF: 0.769 AC: 8138 AN: 10582

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.772 AC: 52490 AN: 68000

Other (OTH) AF: 0.645 AC: 1359 AN: 2108

Alfa AF: 0.723 Hom.: 78533

Bravo AF: 0.624

Asia WGS AF: 0.694 AC: 2411 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.049
DANN	Benign	0.63
PhyloP100		-2.5
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: rs2238092; hg19: chr12-2723266;