rs773528195

Variant names:

• chr12-2115343-G-A
• rs773528195
• NM_000719.7:c.169G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS2

The NM_000719.7(CACNA1C):​c.169G>A​(p.Asp57Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,435,056 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D57V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 7.92
• Publications: 2 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.259G>A	p.Asp87Asn	missense_variant	Exon 2 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.259G>A	p.Asp87Asn	missense_variant	Exon 2 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.259G>A	p.Asp87Asn	missense_variant	Exon 2 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.259G>A	p.Asp87Asn	missense_variant	Exon 2 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.259G>A	p.Asp87Asn	missense_variant	Exon 2 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.259G>A	p.Asp87Asn	missense_variant	Exon 2 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.169G>A	p.Asp57Asn	missense_variant	Exon 2 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.118G>A	p.Asp40Asn	missense_variant	Exon 1 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.169G>A		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000101 AC: 2 AN: 198804 AF XY: 0.0000183

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000341

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: 0.00000348 AC: 5 AN: 1435056 Hom.: 0 Cov.: 32 AF XY: 0.00000702 AC XY: 5 AN XY: 712452

African (AFR) AF: 0.00 AC: 0 AN: 32766

American (AMR) AF: 0.0000247 AC: 1 AN: 40494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25686

East Asian (EAS) AF: 0.00 AC: 0 AN: 37810

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102596

Other (OTH) AF: 0.00 AC: 0 AN: 59522

GnomAD4 genome Cov.: 34

Alfa AF: 0.000509 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000835 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cardiovascular phenotype Uncertain:1

Nov 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D57N variant (also known as c.169G>A), located in coding exon 2 of the CACNA1C gene, results from a G to A substitution at nucleotide position 169. The aspartic acid at codon 57 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Long QT syndrome Benign:1

Apr 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Benign	0.0053
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.56	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	0.98	D
MutationAssessor	Benign	0.94	.;.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.3	D;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	0.55
Sift	Uncertain	0.027	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.86, 0.28, 0.96, 1.0, 0.039, 1.0, 1.0	.;.;D;.;P;B;D;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;.
Vest4		0.58, 0.64, 0.68, 0.66, 0.64, 0.67, 0.65, 0.65, 0.64, 0.65, 0.62, 0.59, 0.66, 0.65, 0.63, 0.64, 0.65, 0.65, 0.64
MutPred		0.37		.;Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);
MVP		0.94
MPC		1.1
ClinPred		0.80	D
GERP RS		5.6
PromoterAI		0.0058	Neutral
gMVP		0.83
Mutation Taster		=39/61	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: rs773528195; hg19: chr12-2224509;