rs1306573144

Variant names:

• chr16-1153776-G-A
• rs1306573144
• NM_021098.3:c.39G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_021098.3(CACNA1H):​c.39G>A​(p.Val13Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000466 in 1,224,094 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 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.876
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 16-1153776-G-A is Benign according to our data. Variant chr16-1153776-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 460104.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.876 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.39G>A	p.Val13Val	synonymous_variant	Exon 2 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.39G>A		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150842 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000512 AC: 55 AN: 1073252 Hom.: 0 Cov.: 32 AF XY: 0.0000531 AC XY: 27 AN XY: 508842

African (AFR) AF: 0.00 AC: 0 AN: 21952

American (AMR) AF: 0.00 AC: 0 AN: 7608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13284

East Asian (EAS) AF: 0.00 AC: 0 AN: 24122

South Asian (SAS) AF: 0.00 AC: 0 AN: 24146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2808

European-Non Finnish (NFE) AF: 0.0000590 AC: 54 AN: 915308

Other (OTH) AF: 0.0000236 AC: 1 AN: 42414

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150842 Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 1 AN XY: 73670

African (AFR) AF: 0.00 AC: 0 AN: 41180

American (AMR) AF: 0.00 AC: 0 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5038

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67596

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Feb 17, 2024

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	-0.63
CADD	Benign	12
DANN	Benign	0.81
PhyloP100		0.88
PromoterAI		-0.0046	Neutral

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: rs1306573144; hg19: chr16-1203776;