12-2605108-C-T

Variant names:

• chr12-2605108-C-T
• rs886039065
• NM_000719.7:c.2988C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_000719.7(CACNA1C):​c.2988C>T​(p.Ile996Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.22

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-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 12-2605108-C-T is Benign according to our data. Variant chr12-2605108-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 264156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.22 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3138C>T	p.Ile1046Ile	synonymous_variant	Exon 24 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3153C>T	p.Ile1051Ile	synonymous_variant	Exon 24 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3048C>T	p.Ile1016Ile	synonymous_variant	Exon 24 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3078C>T	p.Ile1026Ile	synonymous_variant	Exon 23 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3078C>T	p.Ile1026Ile	synonymous_variant	Exon 23 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3078C>T	p.Ile1026Ile	synonymous_variant	Exon 23 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3078C>T	p.Ile1026Ile	synonymous_variant	Exon 23 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3063C>T	p.Ile1021Ile	synonymous_variant	Exon 24 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3048C>T	p.Ile1016Ile	synonymous_variant	Exon 24 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3063C>T	p.Ile1021Ile	synonymous_variant	Exon 24 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2979C>T	p.Ile993Ile	synonymous_variant	Exon 23 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2988C>T	p.Ile996Ile	synonymous_variant	Exon 23 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1595C>T		non_coding_transcript_exon_variant	Exon 21 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1595C>T		3_prime_UTR_variant	Exon 21 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Benign:1

Nov 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jul 15, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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_noAF	Benign	-0.32
CADD	Benign	11
DANN	Benign	0.87

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: rs886039065; hg19: chr12-2714274;