rs200228767

Variant names:

• chr16-1210082-G-T
• rs200228767
• NM_021098.3:c.3792G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-1210082-G-T
• chr16-1210082-G-A
• chr16-1210082-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.3792G>T​(p.Gln1264His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000665 in 1,559,858 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (3 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.408
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015750557).
• BP6: Variant 16-1210082-G-T is Benign according to our data. Variant chr16-1210082-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529635.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000591 (90/152330) while in subpopulation AMR AF = 0.00196 (30/15310). AF 95% confidence interval is 0.00141. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 90 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.3792G>T	p.Gln1264His	missense	Exon 18 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.3792G>T	p.Gln1264His	missense	Exon 18 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.3792G>T	p.Gln1264His	missense	Exon 18 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.3792G>T	p.Gln1264His	missense	Exon 18 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.3792G>T	p.Gln1264His	missense	Exon 18 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000679 AC: 113 AN: 166482 AF XY: 0.000661

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000892

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000674 AC: 948 AN: 1407528 Hom.: 3 Cov.: 34 AF XY: 0.000646 AC XY: 449 AN XY: 695280

African (AFR) AF: 0.000157 AC: 5 AN: 31840

American (AMR) AF: 0.00163 AC: 61 AN: 37374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25276

East Asian (EAS) AF: 0.00 AC: 0 AN: 36264

South Asian (SAS) AF: 0.000176 AC: 14 AN: 79656

European-Finnish (FIN) AF: 0.0000207 AC: 1 AN: 48356

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5702

European-Non Finnish (NFE) AF: 0.000738 AC: 800 AN: 1084696

Other (OTH) AF: 0.00101 AC: 59 AN: 58364

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40 AN XY: 74488

African (AFR) AF: 0.000120 AC: 5 AN: 41572

American (AMR) AF: 0.00196 AC: 30 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68014

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000829 Hom.: 0

Bravo AF: 0.000824

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.00109 AC: 9

ExAC AF: 0.000360 AC: 41

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV (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	Benign	0.16
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.41
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.69
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Polyphen		0.61	P
Vest4		0.20
MutPred		0.77		Gain of helix (P = 0.0325)
MVP		0.98
ClinPred		0.080	T
GERP RS		1.7
PromoterAI		0.0020	Neutral
Varity_R		0.12
gMVP		0.71
Mutation Taster		=82/18	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: rs200228767; hg19: chr16-1260082;