rs200804807

chr16-1202185-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):c.1735G>A(p.Asp579Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000366 in 1,552,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D579E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.88

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009857684).
• BP6: Variant 16-1202185-G-A is Benign according to our data. Variant chr16-1202185-G-A is described in ClinVar as [Benign]. Clinvar id is 460051.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 = 0.00174 (265/152332) while in subpopulation AFR AF= 0.00616 (256/41574). AF 95% confidence interval is 0.00554. There are 0 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 265 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.1735G>A	p.Asp579Asn	missense_variant	9/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1735G>A	p.Asp579Asn	missense_variant	9/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152214 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00618

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000395 AC: 59 AN: 149244 Hom.: 0 AF XY: 0.000346 AC XY: 28 AN XY: 80822

Gnomad AFR exome AF: 0.00614

Gnomad AMR exome AF: 0.000201

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000642

Gnomad SAS exome AF: 0.0000440

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.000217 AC: 304 AN: 1400288 Hom.: 0 Cov.: 36 AF XY: 0.000185 AC XY: 128 AN XY: 691096

Gnomad4 AFR exome AF: 0.00664

Gnomad4 AMR exome AF: 0.000277

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00131

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.0000211

Gnomad4 NFE exome AF: 0.0000167

Gnomad4 OTH exome AF: 0.000275

GnomAD4 genome AF: 0.00174 AC: 265 AN: 152332 Hom.: 0 Cov.: 34 AF XY: 0.00158 AC XY: 118 AN XY: 74486

Gnomad4 AFR AF: 0.00616

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.00191

ESP6500AA AF: 0.00154 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000291 AC: 31

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CACNA1H-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D;D;.
MetaRNN	Benign	0.0099	T;T;T;T
MetaSVM	Uncertain	0.097	D
MutationAssessor	Benign	1.9	L;.;L;L
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.6	D;.;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.035	D;.;D;D
Sift4G	Benign	0.12	T;.;T;T
Polyphen		0.027	B;.;P;P
Vest4		0.40
MVP		0.89
ClinPred		0.019	T
GERP RS		2.8
Varity_R		0.28
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs200804807; hg19: chr16-1252185;