rs1555774889

Variant names:

• chr12-2549962-G-A
• rs1555774889
• NM_000719.7:c.1410G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2549962-G-A
• chr12-2549962-G-T

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.1410G>A​(p.Glu470Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000000688 in 1,452,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.64
• 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=-0.33).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1500G>A	p.Glu500Glu	synonymous_variant	Exon 10 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1575G>A	p.Glu525Glu	synonymous_variant	Exon 11 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1500G>A	p.Glu500Glu	synonymous_variant	Exon 10 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1500G>A	p.Glu500Glu	synonymous_variant	Exon 10 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1500G>A	p.Glu500Glu	synonymous_variant	Exon 10 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1500G>A	p.Glu500Glu	synonymous_variant	Exon 10 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1485G>A	p.Glu495Glu	synonymous_variant	Exon 11 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1485G>A	p.Glu495Glu	synonymous_variant	Exon 11 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1401G>A	p.Glu467Glu	synonymous_variant	Exon 10 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1410G>A	p.Glu470Glu	synonymous_variant	Exon 10 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*17G>A		non_coding_transcript_exon_variant	Exon 8 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*17G>A		3_prime_UTR_variant	Exon 8 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452956 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721762

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.00 AC: 0 AN: 43600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39346

South Asian (SAS) AF: 0.00 AC: 0 AN: 84134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107888

Other (OTH) AF: 0.00 AC: 0 AN: 60114

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	10
DANN	Benign	0.58
PhyloP100		3.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555774889; hg19: chr12-2659128;