rs1544514

Variant names:

• chr12-2449020-G-A
• rs1544514
• NM_000719.7:c.522G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2449020-G-A
• chr12-2449020-G-C
• chr12-2449020-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000719.7(CACNA1C):​c.522G>A​(p.Ala174Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,603,596 control chromosomes in the GnomAD database, including 31,499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2420 hom., cov: 33)
  • Exomes 𝑓: 0.20 (29079 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0370
• Publications: 21 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-2449020-G-A is Benign according to our data. Variant chr12-2449020-G-A is described in ClinVar as Benign. ClinVar VariationId is 93412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.037 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.207 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.522G>A	p.Ala174Ala	synonymous	Exon 4 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.522G>A	p.Ala174Ala	synonymous	Exon 4 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.522G>A	p.Ala174Ala	synonymous	Exon 4 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.522G>A	p.Ala174Ala	synonymous	Exon 4 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.522G>A	p.Ala174Ala	synonymous	Exon 4 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.612G>A	p.Ala204Ala	synonymous	Exon 4 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25617 AN: 151994 Hom.: 2420 Cov.: 33

Gnomad AFR AF: 0.0971

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0615

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.176 AC: 42748 AN: 242448 AF XY: 0.179

Gnomad AFR exome AF: 0.0951

Gnomad AMR exome AF: 0.159

Gnomad ASJ exome AF: 0.290

Gnomad EAS exome AF: 0.0644

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.209

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.196 AC: 284454 AN: 1451484 Hom.: 29079 Cov.: 28 AF XY: 0.196 AC XY: 141705 AN XY: 722124

African (AFR) AF: 0.0942 AC: 3142 AN: 33354

American (AMR) AF: 0.160 AC: 7070 AN: 44170

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 7398 AN: 25922

East Asian (EAS) AF: 0.0719 AC: 2850 AN: 39644

South Asian (SAS) AF: 0.150 AC: 12761 AN: 85270

European-Finnish (FIN) AF: 0.166 AC: 8837 AN: 53226

Middle Eastern (MID) AF: 0.216 AC: 1241 AN: 5746

European-Non Finnish (NFE) AF: 0.208 AC: 229778 AN: 1104136

Other (OTH) AF: 0.190 AC: 11377 AN: 60016

GnomAD4 genome AF: 0.168 AC: 25623 AN: 152112 Hom.: 2420 Cov.: 33 AF XY: 0.166 AC XY: 12325 AN XY: 74372

African (AFR) AF: 0.0970 AC: 4026 AN: 41486

American (AMR) AF: 0.184 AC: 2817 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1012 AN: 3472

East Asian (EAS) AF: 0.0617 AC: 320 AN: 5190

South Asian (SAS) AF: 0.147 AC: 707 AN: 4812

European-Finnish (FIN) AF: 0.167 AC: 1766 AN: 10580

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14272 AN: 67980

Other (OTH) AF: 0.168 AC: 355 AN: 2110

Alfa AF: 0.199 Hom.: 7881

Bravo AF: 0.167

Asia WGS AF: 0.0870 AC: 305 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Cardiovascular phenotype (1)
-	-	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	-0.39
CADD	Benign	13
DANN	Benign	0.78
PhyloP100		0.037
Mutation Taster		=98/2	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: rs1544514; hg19: chr12-2558186; COSMIC: COSV59719439;