12-2549962-G-T

Variant names:

• chr12-2549962-G-T
• rs1555774889
• NM_000719.7:c.1410G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000719.7(CACNA1C):​c.1410G>T​(p.Glu470Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 122) in uniprot entity CAC1C_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31952465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1500G>T	p.Glu500Asp	missense_variant	Exon 10 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1575G>T	p.Glu525Asp	missense_variant	Exon 11 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1500G>T	p.Glu500Asp	missense_variant	Exon 10 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1500G>T	p.Glu500Asp	missense_variant	Exon 10 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1500G>T	p.Glu500Asp	missense_variant	Exon 10 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1500G>T	p.Glu500Asp	missense_variant	Exon 10 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1485G>T	p.Glu495Asp	missense_variant	Exon 11 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1485G>T	p.Glu495Asp	missense_variant	Exon 11 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1401G>T	p.Glu467Asp	missense_variant	Exon 10 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1410G>T	p.Glu470Asp	missense_variant	Exon 10 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*17G>T		non_coding_transcript_exon_variant	Exon 8 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*17G>T		3_prime_UTR_variant	Exon 8 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452956 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721762

Gnomad4 AFR exome AF: 0.00

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: 0.00

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

Dec 05, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with aspartic acid at codon 470 of the CACNA1C protein (p.Glu470Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic 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
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.32	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	0.59	D
MutationAssessor	Benign	0.88	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.7	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	Benign	0.34	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	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99, 0.86, 0.72, 0.99, 0.0040, 1.0, 0.99, 0.47, 0.99, 1.0, 0.025, 0.95	.;D;P;P;D;B;D;D;D;P;D;D;D;D;B;D;.;D;D;.;.;.;P
Vest4		0.49
MutPred		0.18		.;Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);Gain of catalytic residue at V474 (P = 0.0672);
MVP		0.88
MPC		0.96
ClinPred		0.58	D
GERP RS		5.1
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555774889; hg19: chr12-2659128;