rs373335068

Variant names:

• chr12-2556954-C-A
• rs373335068
• NM_000719.7:c.1485C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2556954-C-A
• chr12-2556954-C-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_199460.4(CACNA1C):​c.1485C>A​(p.His495Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,612,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. H495R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CACNA1C NM_199460.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.22
• Publications: 3 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13600987).
• BP6: Variant 12-2556954-C-A is Benign according to our data. Variant chr12-2556954-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190639.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000223 (34/152184) while in subpopulation AFR AF = 0.000821 (34/41426). AF 95% confidence interval is 0.000603. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 34 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.1485C>A	p.His495Gln	missense	Exon 11 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.1485C>A	p.His495Gln	missense	Exon 11 of 47	NP_001161095.1
	CACNA1C	NM_199460.4		c.1485C>A	p.His495Gln	missense	Exon 11 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.1485C>A	p.His495Gln	missense	Exon 11 of 47	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.1485C>A	p.His495Gln	missense	Exon 11 of 47	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.1575C>A	p.His525Gln	missense	Exon 11 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000281 AC: 7 AN: 249262 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1460466 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726640

African (AFR) AF: 0.000658 AC: 22 AN: 33458

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110746

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74340

African (AFR) AF: 0.000821 AC: 34 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000174

ESP6500AA AF: 0.000260 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000414 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	1	-	not provided (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)
-	1	-	Wolff-Parkinson-White pattern (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
CardioboostArm	Benign	0.000083
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Benign	0.70
DEOGEN2	Benign	0.0094	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	-0.85	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.47
Sift	Benign	0.60	T
Sift4G	Benign	0.39	T
Polyphen		0.59	P
Vest4		0.47
MutPred		0.42		Gain of catalytic residue at R492 (P = 0.015)
MVP		0.96
MPC		1.1
ClinPred		0.022	T
GERP RS		1.6
gMVP		0.72
Mutation Taster		=84/16	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: rs373335068; hg19: chr12-2666120;