12-2556960-C-T

Position:

• chr12-2556960-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_000719.7(CACNA1C):​c.1491C>T​(p.Ile497Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,700 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: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.67

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 12-2556960-C-T is Benign according to our data. Variant chr12-2556960-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 456946.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.67 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1581C>T	p.Ile527Ile	synonymous_variant	11/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1491C>T	p.Ile497Ile	synonymous_variant	11/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1656C>T	p.Ile552Ile	synonymous_variant	12/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1491C>T	p.Ile497Ile	synonymous_variant	11/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1491C>T	p.Ile497Ile	synonymous_variant	11/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1491C>T	p.Ile497Ile	synonymous_variant	11/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1581C>T	p.Ile527Ile	synonymous_variant	11/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1581C>T	p.Ile527Ile	synonymous_variant	11/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1581C>T	p.Ile527Ile	synonymous_variant	11/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1581C>T	p.Ile527Ile	synonymous_variant	11/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1491C>T	p.Ile497Ile	synonymous_variant	11/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1566C>T	p.Ile522Ile	synonymous_variant	12/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1491C>T	p.Ile497Ile	synonymous_variant	11/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1566C>T	p.Ile522Ile	synonymous_variant	12/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1491C>T	p.Ile497Ile	synonymous_variant	11/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1491C>T	p.Ile497Ile	synonymous_variant	11/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1491C>T	p.Ile497Ile	synonymous_variant	11/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1491C>T	p.Ile497Ile	synonymous_variant	11/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1482C>T	p.Ile494Ile	synonymous_variant	11/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1491C>T	p.Ile497Ile	synonymous_variant	11/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*98C>T		non_coding_transcript_exon_variant	9/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*98C>T		3_prime_UTR_variant	9/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460700 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726732

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 22, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	11
DANN	Benign	0.76

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: rs750329281; hg19: chr12-2666126;