chr12-2679763-T-C

Position:

• chr12-2679763-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The ENST00000399655.6(CACNA1C):​c.5411T>C​(p.Val1804Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,585,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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. V1804L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CACNA1C ENST00000399655.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.54

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07525095).
• BP6: Variant 12-2679763-T-C is Benign according to our data. Variant chr12-2679763-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411737.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5411T>C	p.Val1804Ala	missense_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5411T>C	p.Val1804Ala	missense_variant	42/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5411T>C	p.Val1804Ala	missense_variant	42/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5411T>C	p.Val1804Ala	missense_variant	42/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5645T>C	p.Val1882Ala	missense_variant	44/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5411T>C	p.Val1804Ala	missense_variant	42/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5378T>C	p.Val1793Ala	missense_variant	41/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5576T>C	p.Val1859Ala	missense_variant	43/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5555T>C	p.Val1852Ala	missense_variant	44/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5534T>C	p.Val1845Ala	missense_variant	42/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5411T>C	p.Val1804Ala	missense_variant	42/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5411T>C	p.Val1804Ala	missense_variant	42/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5501T>C	p.Val1834Ala	missense_variant	42/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5501T>C	p.Val1834Ala	missense_variant	42/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5501T>C	p.Val1834Ala	missense_variant	42/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5501T>C	p.Val1834Ala	missense_variant	42/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5495T>C	p.Val1832Ala	missense_variant	43/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5486T>C	p.Val1829Ala	missense_variant	43/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5471T>C	p.Val1824Ala	missense_variant	43/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5468T>C	p.Val1823Ala	missense_variant	42/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5468T>C	p.Val1823Ala	missense_variant	42/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5468T>C	p.Val1823Ala	missense_variant	42/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5462T>C	p.Val1821Ala	missense_variant	42/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5453T>C	p.Val1818Ala	missense_variant	42/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5435T>C	p.Val1812Ala	missense_variant	41/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5435T>C	p.Val1812Ala	missense_variant	41/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5429T>C	p.Val1810Ala	missense_variant	41/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5411T>C	p.Val1804Ala	missense_variant	42/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5411T>C	p.Val1804Ala	missense_variant	42/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5411T>C	p.Val1804Ala	missense_variant	42/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5411T>C	p.Val1804Ala	missense_variant	42/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5411T>C	p.Val1804Ala	missense_variant	42/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5402T>C	p.Val1801Ala	missense_variant	42/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5378T>C	p.Val1793Ala	missense_variant	41/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

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

GnomAD3 exomes AF: 0.00000982 AC: 2 AN: 203592 Hom.: 0 AF XY: 0.00000905 AC XY: 1 AN XY: 110476

Gnomad AFR exome AF: 0.000177

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000105 AC: 15 AN: 1433794 Hom.: 0 Cov.: 34 AF XY: 0.0000127 AC XY: 9 AN XY: 710254

Gnomad4 AFR exome AF: 0.000336

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000506

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74318

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000250 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 08, 2021

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2023

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
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.80
DEOGEN2	Benign	0.0058	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.075	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.5	.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.96	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.82	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.19
Sift	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.79	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.19
MutPred		0.34		.;.;.;.;.;.;.;.;.;.;Loss of stability (P = 0.0481);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.50
MPC		0.23
ClinPred		0.049	T
GERP RS		0.97
gMVP		0.38

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

Other links and lift over

dbSNP: rs756492434; hg19: chr12-2788929;