rs113869350

Variant names:

• chr12-2115387-G-A
• rs113869350
• NM_000719.7:c.213G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2115387-G-A
• chr12-2115387-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.213G>A​(p.Ala71Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,609,788 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A71A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (52 hom., cov: 34)
  • Exomes 𝑓: 0.0018 (37 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.40
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-2115387-G-A is Benign according to our data. Variant chr12-2115387-G-A is described in ClinVar as Benign. ClinVar VariationId is 238171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1979/152336) while in subpopulation AFR AF = 0.0444 (1848/41576). AF 95% confidence interval is 0.0428. There are 52 homozygotes in GnomAd4. There are 947 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1979 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.213G>A	p.Ala71Ala	synonymous	Exon 2 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.213G>A	p.Ala71Ala	synonymous	Exon 2 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.213G>A	p.Ala71Ala	synonymous	Exon 2 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.213G>A	p.Ala71Ala	synonymous	Exon 2 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.213G>A	p.Ala71Ala	synonymous	Exon 2 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.303G>A	p.Ala101Ala	synonymous	Exon 2 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1969 AN: 152218 Hom.: 51 Cov.: 34

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00329 AC: 792 AN: 240666 AF XY: 0.00243

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00294

Gnomad EAS exome AF: 0.0000568

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000494

Gnomad OTH exome AF: 0.00239

GnomAD4 exome AF: 0.00176 AC: 2559 AN: 1457452 Hom.: 37 Cov.: 32 AF XY: 0.00153 AC XY: 1111 AN XY: 724948

African (AFR) AF: 0.0450 AC: 1506 AN: 33434

American (AMR) AF: 0.00275 AC: 122 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.00357 AC: 93 AN: 26016

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39626

South Asian (SAS) AF: 0.000222 AC: 19 AN: 85750

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51240

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5764

European-Non Finnish (NFE) AF: 0.000476 AC: 529 AN: 1111092

Other (OTH) AF: 0.00438 AC: 264 AN: 60244

GnomAD4 genome AF: 0.0130 AC: 1979 AN: 152336 Hom.: 52 Cov.: 34 AF XY: 0.0127 AC XY: 947 AN XY: 74474

African (AFR) AF: 0.0444 AC: 1848 AN: 41576

American (AMR) AF: 0.00451 AC: 69 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68030

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00484 Hom.: 3

Bravo AF: 0.0146

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.60
PhyloP100		-3.4
PromoterAI		0.0070	Neutral
Mutation Taster		=74/26	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: rs113869350; hg19: chr12-2224553; COSMIC: COSV104405042; COSMIC: COSV104405042;