rs191613214

Variant names:

• chr16-1153830-G-A
• rs191613214
• NM_021098.3:c.93G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1153830-G-A
• chr16-1153830-G-C

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_021098.3(CACNA1H):​c.93G>A​(p.Glu31Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,290,588 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (24 hom., cov: 30)
  • Exomes 𝑓: 0.0011 (39 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.234
• 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: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-1153830-G-A is Benign according to our data. Variant chr16-1153830-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.234 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1759/151202) while in subpopulation AFR AF = 0.0401 (1659/41354). AF 95% confidence interval is 0.0385. There are 24 homozygotes in GnomAd4. There are 834 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1759 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.93G>A	p.Glu31Glu	synonymous	Exon 2 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.93G>A	p.Glu31Glu	synonymous	Exon 2 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.93G>A	p.Glu31Glu	synonymous	Exon 2 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.93G>A	p.Glu31Glu	synonymous	Exon 2 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.93G>A	p.Glu31Glu	synonymous	Exon 2 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1759 AN: 151094 Hom.: 25 Cov.: 30

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00441

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: 0.000162

Gnomad OTH AF: 0.0106

GnomAD2 exomes AF: 0.00148 AC: 8 AN: 5402 AF XY: 0.000845

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.00142

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: 0.0127

GnomAD4 exome AF: 0.00111 AC: 1261 AN: 1139386 Hom.: 39 Cov.: 32 AF XY: 0.000988 AC XY: 542 AN XY: 548742

African (AFR) AF: 0.0474 AC: 1083 AN: 22840

American (AMR) AF: 0.00192 AC: 17 AN: 8838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14810

East Asian (EAS) AF: 0.00 AC: 0 AN: 25566

South Asian (SAS) AF: 0.000101 AC: 4 AN: 39562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26252

Middle Eastern (MID) AF: 0.00365 AC: 11 AN: 3014

European-Non Finnish (NFE) AF: 0.0000294 AC: 28 AN: 952998

Other (OTH) AF: 0.00259 AC: 118 AN: 45506

GnomAD4 genome AF: 0.0116 AC: 1759 AN: 151202 Hom.: 24 Cov.: 30 AF XY: 0.0113 AC XY: 834 AN XY: 73926

African (AFR) AF: 0.0401 AC: 1659 AN: 41354

American (AMR) AF: 0.00440 AC: 67 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5040

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67700

Other (OTH) AF: 0.0105 AC: 22 AN: 2096

Alfa AF: 0.00985 Hom.: 5

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	CACNA1H-related disorder (1)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.7
DANN	Benign	0.88
PhyloP100		-0.23
PromoterAI		0.060	Neutral
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs191613214; hg19: chr16-1203830;