rs587780882

Variant names:

• chr12-2120328-A-G
• rs587780882
• NM_000719.7:c.375A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.375A>G​(p.Pro125Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,514,324 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: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.82
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 12-2120328-A-G is Benign according to our data. Variant chr12-2120328-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.83 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000394 (6/152200) while in subpopulation EAS AF = 0.000963 (5/5194). AF 95% confidence interval is 0.000379. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.465A>G	p.Pro155Pro	synonymous_variant	Exon 3 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.465A>G	p.Pro155Pro	synonymous_variant	Exon 3 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.465A>G	p.Pro155Pro	synonymous_variant	Exon 3 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.465A>G	p.Pro155Pro	synonymous_variant	Exon 3 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.465A>G	p.Pro155Pro	synonymous_variant	Exon 3 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.465A>G	p.Pro155Pro	synonymous_variant	Exon 3 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.375A>G	p.Pro125Pro	synonymous_variant	Exon 3 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.324A>G	p.Pro108Pro	synonymous_variant	Exon 2 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.375A>G		non_coding_transcript_exon_variant	Exon 3 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000601 AC: 15 AN: 249396 AF XY: 0.0000887

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000774

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000117 AC: 16 AN: 1362124 Hom.: 0 Cov.: 24 AF XY: 0.0000146 AC XY: 10 AN XY: 683734

African (AFR) AF: 0.00 AC: 0 AN: 31454

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25550

East Asian (EAS) AF: 0.000306 AC: 12 AN: 39218

South Asian (SAS) AF: 0.00 AC: 0 AN: 84244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5624

European-Non Finnish (NFE) AF: 0.00000196 AC: 2 AN: 1020914

Other (OTH) AF: 0.0000175 AC: 1 AN: 57128

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74356

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 13, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CACNA1C c.375A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6e-05 in 249396 control chromosomes, predominantly at a frequency of 0.00077 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 80 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.375A>G in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Oct 24, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Long QT syndrome Benign:1

Aug 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

May 02, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.0
DANN	Benign	0.73
PhyloP100		1.8

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

Other links and lift over

dbSNP: rs587780882; hg19: chr12-2229494;