12-2504550-C-T

Variant names:

• chr12-2504550-C-T
• rs2238087
• NM_000719.7:c.1114-292C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000719.7(CACNA1C):​c.1114-292C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0782 in 1,483,106 control chromosomes in the GnomAD database, including 4,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (429 hom., cov: 32)
  • Exomes 𝑓: 0.079 (4420 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.556
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-2504550-C-T is Benign according to our data. Variant chr12-2504550-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 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.1114-292C>T		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.1217+11C>T		intron	N/A	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.1114-292C>T		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.1217+11C>T		intron	N/A	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.1114-292C>T		intron	N/A	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.1204-292C>T		intron	N/A	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.0683 AC: 10362 AN: 151768 Hom.: 428 Cov.: 32

Gnomad AFR AF: 0.0406

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0724

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0790

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0795

Gnomad OTH AF: 0.0841

GnomAD2 exomes AF: 0.0760 AC: 18888 AN: 248548 AF XY: 0.0784

Gnomad AFR exome AF: 0.0415

Gnomad AMR exome AF: 0.0506

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.0402

Gnomad NFE exome AF: 0.0818

Gnomad OTH exome AF: 0.0796

GnomAD4 exome AF: 0.0794 AC: 105691 AN: 1331220 Hom.: 4420 Cov.: 21 AF XY: 0.0798 AC XY: 53465 AN XY: 669722

African (AFR) AF: 0.0407 AC: 1259 AN: 30954

American (AMR) AF: 0.0539 AC: 2400 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 3235 AN: 25386

East Asian (EAS) AF: 0.125 AC: 4886 AN: 39066

South Asian (SAS) AF: 0.0747 AC: 6250 AN: 83676

European-Finnish (FIN) AF: 0.0420 AC: 2235 AN: 53226

Middle Eastern (MID) AF: 0.0898 AC: 494 AN: 5504

European-Non Finnish (NFE) AF: 0.0807 AC: 80116 AN: 992780

Other (OTH) AF: 0.0858 AC: 4816 AN: 56104

GnomAD4 genome AF: 0.0682 AC: 10362 AN: 151886 Hom.: 429 Cov.: 32 AF XY: 0.0672 AC XY: 4987 AN XY: 74218

African (AFR) AF: 0.0408 AC: 1690 AN: 41410

American (AMR) AF: 0.0722 AC: 1101 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3468

East Asian (EAS) AF: 0.135 AC: 696 AN: 5162

South Asian (SAS) AF: 0.0782 AC: 375 AN: 4794

European-Finnish (FIN) AF: 0.0412 AC: 435 AN: 10564

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0795 AC: 5400 AN: 67936

Other (OTH) AF: 0.0827 AC: 174 AN: 2104

Alfa AF: 0.0796 Hom.: 1556

Bravo AF: 0.0713

Asia WGS AF: 0.0910 AC: 315 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.9
DANN	Benign	0.91
PhyloP100		-0.56
PromoterAI		0.0034	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2238087; hg19: chr12-2613716; COSMIC: COSV59776774;