rs201756421

Variant names:

• chr12-2486257-T-C
• rs201756421
• NM_000719.7:c.911T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_199460.4(CACNA1C):​c.911T>C​(p.Ile304Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000954 in 1,612,986 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I304V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (1 hom.)
• Consequence: CACNA1C NM_199460.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:7
• Conservation: PhyloP100: 1.42
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013324827).
• BP6: Variant 12-2486257-T-C is Benign according to our data. Variant chr12-2486257-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190631.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000624 (95/152192) while in subpopulation NFE AF = 0.00107 (73/68012). AF 95% confidence interval is 0.000875. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 95 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199460.4. 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.911T>C	p.Ile304Thr	missense	Exon 6 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.911T>C	p.Ile304Thr	missense	Exon 6 of 47	NP_001161095.1
	CACNA1C	NM_199460.4		c.911T>C	p.Ile304Thr	missense	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.911T>C	p.Ile304Thr	missense	Exon 6 of 47	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.911T>C	p.Ile304Thr	missense	Exon 6 of 47	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.1001T>C	p.Ile334Thr	missense	Exon 6 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes AF: 0.000625 AC: 95 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000500 AC: 124 AN: 248032 AF XY: 0.000558

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000945

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000988 AC: 1443 AN: 1460794 Hom.: 1 Cov.: 31 AF XY: 0.000943 AC XY: 685 AN XY: 726604

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.0000895 AC: 4 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 54 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86130

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00119 AC: 1323 AN: 1111284

Other (OTH) AF: 0.000845 AC: 51 AN: 60346

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74418

African (AFR) AF: 0.000169 AC: 7 AN: 41524

American (AMR) AF: 0.000262 AC: 4 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

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

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000884 Hom.: 1

Bravo AF: 0.000578

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000495 AC: 60

EpiCase AF: 0.00109

EpiControl AF: 0.00125

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	2	2	not specified (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	Timothy syndrome (1)
-	1	-	Timothy syndrome;C2678478:Brugada syndrome 3;C5774213:Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;CN260585:Long QT syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
CardioboostArm	Benign	0.0000048
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Benign	0.71
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.20	N
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.0088	T
MutationAssessor	Benign	-0.14	N
PhyloP100		1.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.26
Sift	Benign	0.28	T
Sift4G	Benign	0.74	T
Polyphen		0.018	B
Vest4		0.10
MVP		0.74
MPC		1.3
ClinPred		0.014	T
GERP RS		2.7
gMVP		0.87
Mutation Taster		=91/9	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: rs201756421; hg19: chr12-2595423;