12-2115343-G-A

Position:

chr12-2115343-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BS2

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). Synonymous variant affecting the same amino acid position (i.e. D57D) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:1

Conservation

PhyloP100: 7.92

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.259G>A	p.Asp87Asn	missense_variant	2/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.169G>A	p.Asp57Asn	missense_variant	2/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.259G>A	p.Asp87Asn	missense_variant	2/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.169G>A	p.Asp57Asn	missense_variant	2/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.169G>A	p.Asp57Asn	missense_variant	2/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.169G>A	p.Asp57Asn	missense_variant	2/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.259G>A	p.Asp87Asn	missense_variant	2/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.259G>A	p.Asp87Asn	missense_variant	2/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.259G>A	p.Asp87Asn	missense_variant	2/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.259G>A	p.Asp87Asn	missense_variant	2/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.169G>A	p.Asp57Asn	missense_variant	2/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.169G>A	p.Asp57Asn	missense_variant	2/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.169G>A	p.Asp57Asn	missense_variant	2/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.169G>A	p.Asp57Asn	missense_variant	2/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.169G>A	p.Asp57Asn	missense_variant	2/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.169G>A	p.Asp57Asn	missense_variant	2/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.169G>A	p.Asp57Asn	missense_variant	2/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.169G>A	p.Asp57Asn	missense_variant	2/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.169G>A	p.Asp57Asn	missense_variant	2/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.169G>A	p.Asp57Asn	missense_variant	2/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.169G>A	p.Asp57Asn	missense_variant	2/46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000682152.1 link	c.118G>A	p.Asp40Asn	missense_variant	1/6			ENSP00000506759.1	A0A804HHT8
CACNA1C	ENST00000480911.6 link	n.169G>A		non_coding_transcript_exon_variant	2/27	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000101

AC:

AN:

198804

Hom.:

AF XY:

0.0000183

AC XY:

AN XY:

109506

show subpopulations

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 SAS exome

AF:

0.0000375

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000348

AC:

AN:

1435056

Hom.:

Cov.:

AF XY:

0.00000702

AC XY:

AN XY:

712452

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000247

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000240

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000835

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

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

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

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

M_CAP

Uncertain

0.086

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

MutationAssessor

Benign

0.94

.;.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.

PrimateAI

Pathogenic

0.83

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

GERP RS

5.6

gMVP

0.83

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over