12-2449134-T-C

Variant names:

• chr12-2449134-T-C
• rs1544516
• NM_000719.7:c.617+19T>C

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.617+19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,502,654 control chromosomes in the GnomAD database, including 49,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5659 hom., cov: 33)
  • Exomes 𝑓: 0.25 (43427 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.171
• Publications: 10 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

ENSG00000285734 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-2449134-T-C is Benign according to our data. Variant chr12-2449134-T-C is described in ClinVar as Benign. ClinVar VariationId is 93421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 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.617+19T>C		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.617+19T>C		intron	N/A	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.617+19T>C		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.617+19T>C		intron	N/A	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.617+19T>C		intron	N/A	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.707+19T>C		intron	N/A	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.270 AC: 41012 AN: 151784 Hom.: 5648 Cov.: 33

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.250

GnomAD2 exomes AF: 0.252 AC: 34213 AN: 135580 AF XY: 0.256

Gnomad AFR exome AF: 0.335

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.180

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.250

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.250 AC: 338274 AN: 1350752 Hom.: 43427 Cov.: 27 AF XY: 0.252 AC XY: 167406 AN XY: 663050

African (AFR) AF: 0.333 AC: 9896 AN: 29686

American (AMR) AF: 0.188 AC: 5457 AN: 29046

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 7420 AN: 23738

East Asian (EAS) AF: 0.205 AC: 7208 AN: 35200

South Asian (SAS) AF: 0.294 AC: 20841 AN: 70984

European-Finnish (FIN) AF: 0.243 AC: 11845 AN: 48796

Middle Eastern (MID) AF: 0.255 AC: 1399 AN: 5488

European-Non Finnish (NFE) AF: 0.247 AC: 260051 AN: 1051680

Other (OTH) AF: 0.252 AC: 14157 AN: 56134

GnomAD4 genome AF: 0.270 AC: 41072 AN: 151902 Hom.: 5659 Cov.: 33 AF XY: 0.270 AC XY: 20032 AN XY: 74222

African (AFR) AF: 0.326 AC: 13476 AN: 41360

American (AMR) AF: 0.228 AC: 3479 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1121 AN: 3468

East Asian (EAS) AF: 0.177 AC: 916 AN: 5172

South Asian (SAS) AF: 0.306 AC: 1476 AN: 4816

European-Finnish (FIN) AF: 0.247 AC: 2608 AN: 10568

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17080 AN: 67944

Other (OTH) AF: 0.254 AC: 536 AN: 2110

Alfa AF: 0.272 Hom.: 1073

Bravo AF: 0.271

Asia WGS AF: 0.301 AC: 1044 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)
-	-	1	Timothy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	7.3
DANN	Benign	0.31
PhyloP100		0.17
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: rs1544516; hg19: chr12-2558300; COSMIC: COSV59695535;