chr1-181483780-A-G

Variant names:

• chr1-181483780-A-G
• rs1189578549
• NM_001205293.3:c.36A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001205293.3(CACNA1E):​c.36A>G​(p.Pro12Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,610,394 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 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CACNA1E NM_001205293.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.126

Genes affected

CACNA1E (HGNC:1392): (calcium voltage-gated channel subunit alpha1 E) Voltage-dependent calcium channels are multisubunit complexes consisting of alpha-1, alpha-2, beta, and delta subunits in a 1:1:1:1 ratio. These channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. This gene encodes the alpha-1E subunit of the R-type calcium channels, which belong to the 'high-voltage activated' group that maybe involved in the modulation of firing patterns of neurons important for information processing. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-181483780-A-G is Benign according to our data. Variant chr1-181483780-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1536733.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.126 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.36A>G	p.Pro12Pro	synonymous_variant	Exon 1 of 48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.36A>G	p.Pro12Pro	synonymous_variant	Exon 1 of 48	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.36A>G	p.Pro12Pro	synonymous_variant	Exon 1 of 47	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.36A>G	p.Pro12Pro	synonymous_variant	Exon 1 of 47	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.36A>G	p.Pro12Pro	synonymous_variant	Exon 1 of 46	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.471A>G	p.Pro157Pro	synonymous_variant	Exon 3 of 12	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151732 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.0000121 AC: 3 AN: 248006 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458662 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725628

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.0000671 AC: 3 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5048

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110112

Other (OTH) AF: 0.00 AC: 0 AN: 60216

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151732 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74078

African (AFR) AF: 0.00 AC: 0 AN: 41312

American (AMR) AF: 0.0000656 AC: 1 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67944

Other (OTH) AF: 0.00 AC: 0 AN: 2076

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.3
DANN	Benign	0.71
PhyloP100		-0.13
PromoterAI		0.012	Neutral
Mutation Taster		=299/1	polymorphism

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

Publications

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Other links and lift over

dbSNP: rs1189578549; hg19: chr1-181452916;