ENST00000711482.1:c.6166C>G

Variant names:

• chr16-1220205-C-G
• rs59297244
• ENST00000711482.1:c.6166C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000711482.1(CACNA1H):​c.6166C>G​(p.Arg2056Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2056Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CACNA1H ENST00000711482.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.99
• Publications: 0 publications found

Genes affected

CACNA1H (HGNC:1395): (calcium voltage-gated channel subunit alpha1 H) This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]

CACNA1H Gene-Disease associations (from GenCC):

• hyperaldosteronism, familial, type IV

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, childhood absence, susceptibility to, 6

  Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000711482.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.6273C>G	p.Ala2091Ala	synonymous	Exon 35 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.6255C>G	p.Ala2085Ala	synonymous	Exon 34 of 34	NP_001005407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000711482.1		c.6166C>G	p.Arg2056Gly	missense	Exon 36 of 36	ENSP00000518771.1
	CACNA1H	ENST00000711485.1		c.6115C>G	p.Arg2039Gly	missense	Exon 35 of 35	ENSP00000518774.1
	CACNA1H	ENST00000711455.1		c.6088C>G	p.Arg2030Gly	missense	Exon 36 of 36	ENSP00000518768.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1404604 Hom.: 0 Cov.: 73 AF XY: 0.00 AC XY: 0 AN XY: 695958

African (AFR) AF: 0.00 AC: 0 AN: 29630

American (AMR) AF: 0.00 AC: 0 AN: 37424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23484

East Asian (EAS) AF: 0.00 AC: 0 AN: 36802

South Asian (SAS) AF: 0.00 AC: 0 AN: 78862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1088908

Other (OTH) AF: 0.00 AC: 0 AN: 58026

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.012
DANN	Benign	0.43
PhyloP100		-5.0

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: rs59297244; hg19: chr16-1270205;