NM_000719.7:c.724C>T

Variant names:

• chr12-2457673-C-T
• rs200800133
• NM_000719.7:c.724C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.724C>T​(p.Leu242Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,603,754 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L242L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.00
• Publications: 2 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=-0.42).
• BP6: Variant 12-2457673-C-T is Benign according to our data. Variant chr12-2457673-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 264146.
• BP7: Synonymous conserved (PhyloP=2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00112 (170/152352) while in subpopulation AFR AF = 0.00361 (150/41586). AF 95% confidence interval is 0.00314. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 170 AD gene.

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.724C>T	p.Leu242Leu	synonymous	Exon 5 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.724C>T	p.Leu242Leu	synonymous	Exon 5 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.724C>T	p.Leu242Leu	synonymous	Exon 5 of 50	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.724C>T	p.Leu242Leu	synonymous	Exon 5 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.724C>T	p.Leu242Leu	synonymous	Exon 5 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.814C>T	p.Leu272Leu	synonymous	Exon 5 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000249 AC: 60 AN: 240762 AF XY: 0.000183

Gnomad AFR exome AF: 0.00301

Gnomad AMR exome AF: 0.000373

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000121 AC: 175 AN: 1451402 Hom.: 1 Cov.: 30 AF XY: 0.000107 AC XY: 77 AN XY: 721852

African (AFR) AF: 0.00340 AC: 111 AN: 32694

American (AMR) AF: 0.000376 AC: 16 AN: 42512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25616

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.00 AC: 0 AN: 85116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.0000244 AC: 27 AN: 1107776

Other (OTH) AF: 0.000351 AC: 21 AN: 59776

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000966 AC XY: 72 AN XY: 74506

African (AFR) AF: 0.00361 AC: 150 AN: 41586

American (AMR) AF: 0.00124 AC: 19 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000480 Hom.: 0

Bravo AF: 0.00142

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism

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: rs200800133; hg19: chr12-2566839; COSMIC: COSV59763584;