rs112532048

Variant names:

• chr12-2585485-C-T
• rs112532048
• NM_000719.7:c.2449C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000719.7(CACNA1C):​c.2449C>T​(p.Pro817Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00409 in 1,561,540 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P817P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (12 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 5.63
• Publications: 23 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006192893).
• BP6: Variant 12-2585485-C-T is Benign according to our data. Variant chr12-2585485-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00264 (402/152310) while in subpopulation NFE AF = 0.00456 (310/68028). AF 95% confidence interval is 0.00414. There are 2 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 402 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.2449C>T	p.Pro817Ser	missense	Exon 17 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.2449C>T	p.Pro817Ser	missense	Exon 17 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.2449C>T	p.Pro817Ser	missense	Exon 17 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.2449C>T	p.Pro817Ser	missense	Exon 17 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.2449C>T	p.Pro817Ser	missense	Exon 17 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.2539C>T	p.Pro847Ser	missense	Exon 17 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 402 AN: 152192 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00456

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00233 AC: 395 AN: 169644 AF XY: 0.00217

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000293

Gnomad NFE exome AF: 0.00438

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00424 AC: 5978 AN: 1409230 Hom.: 12 Cov.: 31 AF XY: 0.00410 AC XY: 2855 AN XY: 696258

African (AFR) AF: 0.000740 AC: 24 AN: 32444

American (AMR) AF: 0.00141 AC: 52 AN: 36776

Ashkenazi Jewish (ASJ) AF: 0.00399 AC: 100 AN: 25044

East Asian (EAS) AF: 0.00 AC: 0 AN: 37262

South Asian (SAS) AF: 0.000276 AC: 22 AN: 79590

European-Finnish (FIN) AF: 0.000520 AC: 26 AN: 49996

Middle Eastern (MID) AF: 0.000361 AC: 2 AN: 5538

European-Non Finnish (NFE) AF: 0.00512 AC: 5553 AN: 1084226

Other (OTH) AF: 0.00341 AC: 199 AN: 58354

GnomAD4 genome AF: 0.00264 AC: 402 AN: 152310 Hom.: 2 Cov.: 33 AF XY: 0.00216 AC XY: 161 AN XY: 74484

African (AFR) AF: 0.00123 AC: 51 AN: 41570

American (AMR) AF: 0.00124 AC: 19 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00456 AC: 310 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00402 Hom.: 5

Bravo AF: 0.00261

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000738 AC: 3

ESP6500EA AF: 0.00468 AC: 39

ExAC AF: 0.00194 AC: 229

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	CACNA1C-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Long QT syndrome (1)
-	-	1	Timothy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0062	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	0.92	L
PhyloP100		5.6
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.34
Sift	Benign	0.26	T
Sift4G	Benign	0.23	T
Polyphen		0.78	P
Vest4		0.38
MVP		0.72
MPC		1.9
ClinPred		0.020	T
GERP RS		6.0
gMVP		0.37
Mutation Taster		=82/18	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: rs112532048; hg19: chr12-2694651; COSMIC: COSV99046735;