12-2653904-G-C

Variant names:

• chr12-2653904-G-C
• rs111442547
• NM_000719.7:c.4140+4G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000719.7(CACNA1C):​c.4140+4G>C variant causes a splice region, intron 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. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 splice_region, intron
• Scores: Splicing: ADA: 0.0002500
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• long QT syndrome 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
• Brugada syndrome 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4374+4G>C		splice_region_variant, intron_variant	Intron 35 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4107+4G>C		splice_region_variant, intron_variant	Intron 32 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4305+4G>C		splice_region_variant, intron_variant	Intron 34 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4284+4G>C		splice_region_variant, intron_variant	Intron 35 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4206+4G>C		splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4230+4G>C		splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4230+4G>C		splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4230+4G>C		splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4230+4G>C		splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4224+4G>C		splice_region_variant, intron_variant	Intron 34 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4215+4G>C		splice_region_variant, intron_variant	Intron 34 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4200+4G>C		splice_region_variant, intron_variant	Intron 34 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4191+4G>C		splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4182+4G>C		splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4107+4G>C		splice_region_variant, intron_variant	Intron 32 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4107+4G>C		splice_region_variant, intron_variant	Intron 32 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4101+4G>C		splice_region_variant, intron_variant	Intron 32 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4140+4G>C		splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4131+4G>C		splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4107+4G>C		splice_region_variant, intron_variant	Intron 32 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Benign	0.92
PhyloP100		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.11
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

Other links and lift over

dbSNP: rs111442547; hg19: chr12-2763070;