rs1555825459

Variant names:

• chr12-2581677-C-T
• rs1555825459
• NM_000719.7:c.1983C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000719.7(CACNA1C):​c.1983C>T​(p.Phe661Phe) 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: 29)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.78
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 12-2581677-C-T is Benign according to our data. Variant chr12-2581677-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 527115.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.78 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2073C>T	p.Phe691Phe	synonymous_variant	Exon 14 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2148C>T	p.Phe716Phe	synonymous_variant	Exon 15 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2073C>T	p.Phe691Phe	synonymous_variant	Exon 14 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2073C>T	p.Phe691Phe	synonymous_variant	Exon 14 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2073C>T	p.Phe691Phe	synonymous_variant	Exon 14 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2073C>T	p.Phe691Phe	synonymous_variant	Exon 14 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2058C>T	p.Phe686Phe	synonymous_variant	Exon 15 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2058C>T	p.Phe686Phe	synonymous_variant	Exon 15 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1974C>T	p.Phe658Phe	synonymous_variant	Exon 14 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1983C>T	p.Phe661Phe	synonymous_variant	Exon 14 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*590C>T		non_coding_transcript_exon_variant	Exon 12 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*590C>T		3_prime_UTR_variant	Exon 12 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Benign:1

Mar 12, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.72
PhyloP100		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1555825459; hg19: chr12-2690843;