rs1555857966

Variant names:

• chr12-2595884-C-G
• rs1555857966
• NM_000719.7:c.2674C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000719.7(CACNA1C):​c.2674C>G​(p.Gln892Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000719.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28196794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2764C>G	p.Gln922Glu	missense_variant	Exon 20 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2839C>G	p.Gln947Glu	missense_variant	Exon 21 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2764C>G	p.Gln922Glu	missense_variant	Exon 20 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2764C>G	p.Gln922Glu	missense_variant	Exon 20 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2764C>G	p.Gln922Glu	missense_variant	Exon 20 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2764C>G	p.Gln922Glu	missense_variant	Exon 20 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2749C>G	p.Gln917Glu	missense_variant	Exon 21 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2749C>G	p.Gln917Glu	missense_variant	Exon 21 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2665C>G	p.Gln889Glu	missense_variant	Exon 20 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2674C>G	p.Gln892Glu	missense_variant	Exon 20 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1281C>G		non_coding_transcript_exon_variant	Exon 18 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1281C>G		3_prime_UTR_variant	Exon 18 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461282 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726978

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44706

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: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111742

Other (OTH) AF: 0.00 AC: 0 AN: 60362

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Sep 29, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine with glutamic acid at codon 892 of the CACNA1C protein (p.Gln892Glu). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1C-related disease. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
CardioboostArm	Benign	0.000081
BayesDel_addAF	Benign	0.0069	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.64	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.1	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.043, 0.0030, 0.0070, 0.089, 0.052, 0.034, 0.071, 0.33, 0.029, 0.081, 0.37	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;B;.;B
Vest4		0.48
MutPred		0.60		.;Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);
MVP		0.76
MPC		1.1
ClinPred		0.25	T
GERP RS		4.9
gMVP		0.72
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: rs1555857966; hg19: chr12-2705050;