NM_000719.7:c.2548_2550dupGAG

Variant names:

• chr12-2593223-T-TGAG
• rs575583988
• NM_000719.7:c.2548_2550dupGAG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP3

The NM_000719.7(CACNA1C):​c.2548_2550dupGAG​(p.Glu850dup) variant causes a conservative inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P851P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 7 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000719.7
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000719.7. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2638_2640dupGAG	p.Glu880dup	conservative_inframe_insertion	Exon 19 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2713_2715dupGAG	p.Glu905dup	conservative_inframe_insertion	Exon 20 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2638_2640dupGAG	p.Glu880dup	conservative_inframe_insertion	Exon 19 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2638_2640dupGAG	p.Glu880dup	conservative_inframe_insertion	Exon 19 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2638_2640dupGAG	p.Glu880dup	conservative_inframe_insertion	Exon 19 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2638_2640dupGAG	p.Glu880dup	conservative_inframe_insertion	Exon 19 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2623_2625dupGAG	p.Glu875dup	conservative_inframe_insertion	Exon 20 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2623_2625dupGAG	p.Glu875dup	conservative_inframe_insertion	Exon 20 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2539_2541dupGAG	p.Glu847dup	conservative_inframe_insertion	Exon 19 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2548_2550dupGAG	p.Glu850dup	conservative_inframe_insertion	Exon 19 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1155_*1157dupGAG		non_coding_transcript_exon_variant	Exon 17 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1155_*1157dupGAG		3_prime_UTR_variant	Exon 17 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs575583988; hg19: chr12-2702389;