rs200227029

Positions:

• chr12-2688557-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000719.7(CACNA1C):​c.5895C>T​(p.Pro1965Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.108

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-2688557-C-T is Benign according to our data. Variant chr12-2688557-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 215772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.108 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5895C>T	p.Pro1965Pro	synonymous_variant	46/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5895C>T	p.Pro1965Pro	synonymous_variant	46/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5895C>T	p.Pro1965Pro	synonymous_variant	46/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5895C>T	p.Pro1965Pro	synonymous_variant	46/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6234C>T	p.Pro2078Pro	synonymous_variant	49/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6108C>T	p.Pro2036Pro	synonymous_variant	47/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6075C>T	p.Pro2025Pro	synonymous_variant	46/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6060C>T	p.Pro2020Pro	synonymous_variant	47/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6039C>T	p.Pro2013Pro	synonymous_variant	48/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6018C>T	p.Pro2006Pro	synonymous_variant	46/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6000C>T	p.Pro2000Pro	synonymous_variant	47/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6000C>T	p.Pro2000Pro	synonymous_variant	47/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5985C>T	p.Pro1995Pro	synonymous_variant	46/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5985C>T	p.Pro1995Pro	synonymous_variant	46/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5985C>T	p.Pro1995Pro	synonymous_variant	46/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5985C>T	p.Pro1995Pro	synonymous_variant	46/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5979C>T	p.Pro1993Pro	synonymous_variant	47/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5970C>T	p.Pro1990Pro	synonymous_variant	47/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5955C>T	p.Pro1985Pro	synonymous_variant	47/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5952C>T	p.Pro1984Pro	synonymous_variant	46/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5952C>T	p.Pro1984Pro	synonymous_variant	46/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5952C>T	p.Pro1984Pro	synonymous_variant	46/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5946C>T	p.Pro1982Pro	synonymous_variant	46/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5937C>T	p.Pro1979Pro	synonymous_variant	46/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5919C>T	p.Pro1973Pro	synonymous_variant	45/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5919C>T	p.Pro1973Pro	synonymous_variant	45/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5913C>T	p.Pro1971Pro	synonymous_variant	45/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5895C>T	p.Pro1965Pro	synonymous_variant	46/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5895C>T	p.Pro1965Pro	synonymous_variant	46/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5895C>T	p.Pro1965Pro	synonymous_variant	46/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5895C>T	p.Pro1965Pro	synonymous_variant	46/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5895C>T	p.Pro1965Pro	synonymous_variant	46/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5886C>T	p.Pro1962Pro	synonymous_variant	46/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5862C>T	p.Pro1954Pro	synonymous_variant	45/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000282 AC: 7 AN: 247874 Hom.: 0 AF XY: 0.0000371 AC XY: 5 AN XY: 134692

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

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: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461640 Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000624 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.4
DANN	Benign	0.77

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: rs200227029; hg19: chr12-2797723;