rs112315742

Variant names:

• chr12-2486117-C-T
• rs112315742
• NM_000719.7:c.771C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.771C>T​(p.Val257Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,607,766 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (19 hom., cov: 31)
  • Exomes 𝑓: 0.00090 (24 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.182
• Publications: 1 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, ClinGen
• 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: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 12-2486117-C-T is Benign according to our data. Variant chr12-2486117-C-T is described in ClinVar as Benign. ClinVar VariationId is 93423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.182 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00839 (1277/152270) while in subpopulation AFR AF = 0.0291 (1209/41546). AF 95% confidence interval is 0.0277. There are 19 homozygotes in GnomAd4. There are 614 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1277 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.771C>T	p.Val257Val	synonymous	Exon 6 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.771C>T	p.Val257Val	synonymous	Exon 6 of 47	NP_001161095.1
	CACNA1C	NM_199460.4		c.771C>T	p.Val257Val	synonymous	Exon 6 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.771C>T	p.Val257Val	synonymous	Exon 6 of 47	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.771C>T	p.Val257Val	synonymous	Exon 6 of 47	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.861C>T	p.Val287Val	synonymous	Exon 6 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1276 AN: 152152 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00228 AC: 556 AN: 244228 AF XY: 0.00170

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.000999

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.0000724

Gnomad OTH exome AF: 0.00169

GnomAD4 exome AF: 0.000899 AC: 1309 AN: 1455496 Hom.: 24 Cov.: 31 AF XY: 0.000780 AC XY: 564 AN XY: 723414

African (AFR) AF: 0.0335 AC: 1118 AN: 33402

American (AMR) AF: 0.00126 AC: 56 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25706

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84874

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53172

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5724

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1108438

Other (OTH) AF: 0.00180 AC: 108 AN: 60118

GnomAD4 genome AF: 0.00839 AC: 1277 AN: 152270 Hom.: 19 Cov.: 31 AF XY: 0.00825 AC XY: 614 AN XY: 74454

African (AFR) AF: 0.0291 AC: 1209 AN: 41546

American (AMR) AF: 0.00320 AC: 49 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68036

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00432 Hom.: 6

Bravo AF: 0.0101

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.7
DANN	Benign	0.76
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism

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: rs112315742; hg19: chr12-2595283;