rs747533547

Variant names:

• chr12-2610625-G-A
• rs747533547
• NM_000719.7:c.3643G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2610625-G-A
• chr12-2610625-G-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.3643G>A​(p.Val1215Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 8.06
• Publications: 4 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: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876
• BP6: Variant 12-2610625-G-A is Benign according to our data. Variant chr12-2610625-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526954.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3793G>A	p.Val1265Met	missense_variant	Exon 29 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3808G>A	p.Val1270Met	missense_variant	Exon 29 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3703G>A	p.Val1235Met	missense_variant	Exon 29 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3733G>A	p.Val1245Met	missense_variant	Exon 28 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3733G>A	p.Val1245Met	missense_variant	Exon 28 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3733G>A	p.Val1245Met	missense_variant	Exon 28 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3733G>A	p.Val1245Met	missense_variant	Exon 28 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3718G>A	p.Val1240Met	missense_variant	Exon 29 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3703G>A	p.Val1235Met	missense_variant	Exon 29 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3718G>A	p.Val1240Met	missense_variant	Exon 29 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3634G>A	p.Val1212Met	missense_variant	Exon 28 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3643G>A	p.Val1215Met	missense_variant	Exon 28 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*2250G>A		non_coding_transcript_exon_variant	Exon 26 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*2250G>A		3_prime_UTR_variant	Exon 26 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250456 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:1

Oct 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs747533547, gnomAD 0.006%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 526954). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1215 of the CACNA1C protein (p.Val1215Met). -

Cardiovascular phenotype Benign:1

Aug 29, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
CardioboostArm	Uncertain	0.20
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.090	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.1	.;.;.;.;.;.;.;.;.;.;.;L;L;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		8.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.5	D;D;N;D;D;D;D;D;D;D;D;D;D;D;N;D;D;D;D;D;D;D;N;.
REVEL	Pathogenic	0.87
Sift	Benign	0.062	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Uncertain	0.036	D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;T
Polyphen		0.98, 1.0, 0.99, 0.97, 1.0, 1.0, 0.99	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D;.
Vest4		0.78
MVP		0.88
MPC		1.1
ClinPred		0.84	D
GERP RS		5.1
gMVP		0.93
Mutation Taster		=12/88	disease causing

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: rs747533547; hg19: chr12-2719791; COSMIC: COSV59700086; COSMIC: COSV59700086;