rs56885166

Variant names:

• chr16-1220585-G-A
• rs56885166
• NM_021098.3:c.6653G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1220585-G-A
• chr16-1220585-G-T

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.6653G>A​(p.Arg2218His) variant causes a missense change. The variant allele was found at a frequency of 0.00206 in 1,544,136 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2218C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (2 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.23
• Publications: 4 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=0.030005485).
• BP6: Variant 16-1220585-G-A is Benign according to our data. Variant chr16-1220585-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0013 (198/152140) while in subpopulation NFE AF = 0.00234 (159/67922). AF 95% confidence interval is 0.00204. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 198 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.6653G>A	p.Arg2218His	missense	Exon 35 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.6635G>A	p.Arg2212His	missense	Exon 34 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.6653G>A	p.Arg2218His	missense	Exon 35 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.6668G>A	p.Arg2223His	missense	Exon 34 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.6638G>A	p.Arg2213His	missense	Exon 34 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00151 AC: 267 AN: 177406 AF XY: 0.00145

Gnomad AFR exome AF: 0.000390

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.000218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000429

Gnomad NFE exome AF: 0.00277

Gnomad OTH exome AF: 0.00217

GnomAD4 exome AF: 0.00214 AC: 2981 AN: 1391996 Hom.: 2 Cov.: 35 AF XY: 0.00204 AC XY: 1404 AN XY: 687400

African (AFR) AF: 0.000294 AC: 9 AN: 30650

American (AMR) AF: 0.000606 AC: 19 AN: 31346

Ashkenazi Jewish (ASJ) AF: 0.000187 AC: 4 AN: 21422

East Asian (EAS) AF: 0.00 AC: 0 AN: 39208

South Asian (SAS) AF: 0.000107 AC: 8 AN: 74620

European-Finnish (FIN) AF: 0.000812 AC: 39 AN: 48004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5416

European-Non Finnish (NFE) AF: 0.00261 AC: 2825 AN: 1084082

Other (OTH) AF: 0.00135 AC: 77 AN: 57248

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000995 AC XY: 74 AN XY: 74396

African (AFR) AF: 0.000506 AC: 21 AN: 41530

American (AMR) AF: 0.000849 AC: 13 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00234 AC: 159 AN: 67922

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00124

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000603 AC: 2

ESP6500EA AF: 0.00270 AC: 20

ExAC AF: 0.00170 AC: 199

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.34
MVP		0.77
ClinPred		0.055	T
GERP RS		4.8
Varity_R		0.29
gMVP		0.26
Mutation Taster		=65/35	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: rs56885166; hg19: chr16-1270585; COSMIC: COSV52357509; COSMIC: COSV52357509;