rs58110336

Variant names:

• chr16-1212014-C-T
• rs58110336
• ENST00000711450.1:c.4573C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 2P and 18B. PM1 BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000711450.1(CACNA1H):​c.4573C>T​(p.Arg1525Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,552 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/7 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (19 hom.)
• Consequence: CACNA1H ENST00000711450.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.314
• Publications: 1 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 -16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 7 uncertain in ENST00000711450.1
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 16-1212014-C-T is Benign according to our data. Variant chr16-1212014-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00823 (1254/152344) while in subpopulation AFR AF = 0.0286 (1188/41566). AF 95% confidence interval is 0.0272. There are 14 homozygotes in GnomAd4. There are 568 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1254 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000711450.1. 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.4635C>T	p.Phe1545Phe	synonymous	Exon 25 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.4635C>T	p.Phe1545Phe	synonymous	Exon 25 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000711450.1		c.4573C>T	p.Arg1525Cys	missense	Exon 25 of 35	ENSP00000518762.1	A0AAA9YHS5
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.4635C>T	p.Phe1545Phe	synonymous	Exon 25 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.4635C>T	p.Phe1545Phe	synonymous	Exon 25 of 34	ENSP00000454990.2	H3BNT0

Frequencies

GnomAD3 genomes AF: 0.00822 AC: 1252 AN: 152226 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

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: 0.0000882

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00225 AC: 560 AN: 249104 AF XY: 0.00158

Gnomad AFR exome AF: 0.0313

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000820 AC: 1198 AN: 1461208 Hom.: 19 Cov.: 35 AF XY: 0.000718 AC XY: 522 AN XY: 726910

African (AFR) AF: 0.0285 AC: 953 AN: 33462

American (AMR) AF: 0.00186 AC: 83 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5668

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111678

Other (OTH) AF: 0.00192 AC: 116 AN: 60328

GnomAD4 genome AF: 0.00823 AC: 1254 AN: 152344 Hom.: 14 Cov.: 33 AF XY: 0.00762 AC XY: 568 AN XY: 74494

African (AFR) AF: 0.0286 AC: 1188 AN: 41566

American (AMR) AF: 0.00281 AC: 43 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00399 Hom.: 2

Bravo AF: 0.00919

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_noAF	Benign	-0.32
CADD	Benign	10
DANN	Benign	0.92
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs58110336; hg19: chr16-1262014;