rs201777030

Positions:

• chr12-2685771-C-A
• chr12-2685771-C-G
• chr12-2685771-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000719.7(CACNA1C):​c.5609C>A​(p.Thr1870Lys) 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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1870M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.01

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.2583118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5609C>A	p.Thr1870Lys	missense_variant	44/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5609C>A	p.Thr1870Lys	missense_variant	44/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5609C>A	p.Thr1870Lys	missense_variant	44/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5609C>A	p.Thr1870Lys	missense_variant	44/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5948C>A	p.Thr1983Lys	missense_variant	47/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5822C>A	p.Thr1941Lys	missense_variant	45/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5789C>A	p.Thr1930Lys	missense_variant	44/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5774C>A	p.Thr1925Lys	missense_variant	45/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5753C>A	p.Thr1918Lys	missense_variant	46/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5732C>A	p.Thr1911Lys	missense_variant	44/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5714C>A	p.Thr1905Lys	missense_variant	45/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5714C>A	p.Thr1905Lys	missense_variant	45/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5699C>A	p.Thr1900Lys	missense_variant	44/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5699C>A	p.Thr1900Lys	missense_variant	44/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5699C>A	p.Thr1900Lys	missense_variant	44/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5699C>A	p.Thr1900Lys	missense_variant	44/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5693C>A	p.Thr1898Lys	missense_variant	45/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5684C>A	p.Thr1895Lys	missense_variant	45/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5669C>A	p.Thr1890Lys	missense_variant	45/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5666C>A	p.Thr1889Lys	missense_variant	44/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5666C>A	p.Thr1889Lys	missense_variant	44/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5666C>A	p.Thr1889Lys	missense_variant	44/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5660C>A	p.Thr1887Lys	missense_variant	44/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5651C>A	p.Thr1884Lys	missense_variant	44/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5633C>A	p.Thr1878Lys	missense_variant	43/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5633C>A	p.Thr1878Lys	missense_variant	43/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5627C>A	p.Thr1876Lys	missense_variant	43/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5609C>A	p.Thr1870Lys	missense_variant	44/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5609C>A	p.Thr1870Lys	missense_variant	44/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5609C>A	p.Thr1870Lys	missense_variant	44/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5609C>A	p.Thr1870Lys	missense_variant	44/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5609C>A	p.Thr1870Lys	missense_variant	44/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5600C>A	p.Thr1867Lys	missense_variant	44/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5576C>A	p.Thr1859Lys	missense_variant	43/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long qt syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 24, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with long QT syndrome 8 (MIM#618447) and Timothy syndrome (MIM#601005). Missense variants result in loss of channel inactivation and increased current (OMIM, PMID: 25260352). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Two alternative amino acid changes at the same position have been observed in gnomAD (highest allele count for p.(Thr1870Met), v2 and v3: 390 heterozygotes, 1 homozygote). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated voltage-gated calcium channel subunit alpha, C-term domain (NCBI). (I) 0709 - Another missense variant comparable to the one identified in this case has limited previous evidence for being benign. p.(Thr1870Met) has been reported as benign or likely benign by multiple clinical testing laboratories (ClinVar). (SB) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.010	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.086
Eigen_PC	Benign	-0.072
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.26	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	-0.78	T
PrimateAI	Benign	0.47	T
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;.
REVEL	Benign	0.18
Sift	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.81, 0.0010, 0.43, 0.010, 0.71, 0.30, 0.0, 0.66, 0.19, 0.43, 0.52, 0.63, 0.45	.;P;B;B;B;P;B;B;B;P;B;B;P;B;B;.;B;P;.;.;.;B;.
Vest4		0.48
MVP		0.41
MPC		0.26
ClinPred		0.89	D
GERP RS		4.3
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-2794937;