rs59935412

Variant names:

• chr16-1218604-C-T
• rs59935412
• NM_021098.3:c.5840C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-1218604-C-T
• chr16-1218604-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.5840C>T​(p.Pro1947Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,565,184 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1947P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0056 (11 hom., cov: 31)
  • Exomes 𝑓: 0.00053 (4 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.42
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006367117).
• BP6: Variant 16-1218604-C-T is Benign according to our data. Variant chr16-1218604-C-T is described in ClinVar as Benign. ClinVar VariationId is 460154.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 = 0.00561 (853/152074) while in subpopulation AFR AF = 0.0192 (795/41474). AF 95% confidence interval is 0.0181. There are 11 homozygotes in GnomAd4. There are 402 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 853 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.5840C>T	p.Pro1947Leu	missense	Exon 33 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.5822C>T	p.Pro1941Leu	missense	Exon 32 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.5840C>T	p.Pro1947Leu	missense	Exon 33 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.5855C>T	p.Pro1952Leu	missense	Exon 32 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.5858C>T	p.Pro1953Leu	missense	Exon 32 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 851 AN: 151956 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

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: 0.0000735

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00125 AC: 219 AN: 175698 AF XY: 0.000868

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000549

Gnomad OTH exome AF: 0.00106

GnomAD4 exome AF: 0.000534 AC: 754 AN: 1413110 Hom.: 4 Cov.: 38 AF XY: 0.000462 AC XY: 323 AN XY: 698412

African (AFR) AF: 0.0176 AC: 572 AN: 32522

American (AMR) AF: 0.00128 AC: 48 AN: 37636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25240

East Asian (EAS) AF: 0.00 AC: 0 AN: 37224

South Asian (SAS) AF: 0.0000498 AC: 4 AN: 80250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48802

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5692

European-Non Finnish (NFE) AF: 0.0000313 AC: 34 AN: 1087188

Other (OTH) AF: 0.00154 AC: 90 AN: 58556

GnomAD4 genome AF: 0.00561 AC: 853 AN: 152074 Hom.: 11 Cov.: 31 AF XY: 0.00541 AC XY: 402 AN XY: 74328

African (AFR) AF: 0.0192 AC: 795 AN: 41474

American (AMR) AF: 0.00307 AC: 47 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67978

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00262 Hom.: 2

Bravo AF: 0.00652

ESP6500AA AF: 0.0131 AC: 51

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00126 AC: 147

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0064	T
MetaSVM	Uncertain	0.029	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.23
Sift	Benign	0.084	T
Sift4G	Benign	0.22	T
Polyphen		0.013	B
Vest4		0.38
MVP		0.84
ClinPred		0.0092	T
GERP RS		-0.34
Varity_R		0.090
gMVP		0.52
Mutation Taster		=97/3	polymorphism

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: rs59935412; hg19: chr16-1268604; COSMIC: COSV52354042; COSMIC: COSV52354042;