rs58173258

Variant names:

• chr16-1206126-G-A
• rs58173258
• NM_021098.3:c.2626G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.2626G>A​(p.Ala876Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,583,716 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4 O:2
• Conservation: PhyloP100: 1.18

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01942408).
• BP6: Variant 16-1206126-G-A is Benign according to our data. Variant chr16-1206126-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2706.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=1, not_provided=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00162 (247/152358) while in subpopulation AMR AF= 0.00372 (57/15310). AF 95% confidence interval is 0.00295. There are 0 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 247 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.2626G>A	p.Ala876Thr	missense_variant	Exon 12 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.2626G>A	p.Ala876Thr	missense_variant	Exon 11 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.2587G>A	p.Ala863Thr	missense_variant	Exon 12 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.2626G>A		non_coding_transcript_exon_variant	Exon 12 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*539G>A		non_coding_transcript_exon_variant	Exon 12 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*539G>A		3_prime_UTR_variant	Exon 12 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 247 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.0451

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000658

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00117 AC: 236 AN: 201770 Hom.: 0 AF XY: 0.00112 AC XY: 123 AN XY: 109902

Gnomad AFR exome AF: 0.000535

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.00142

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000622

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.00158 AC: 2260 AN: 1431358 Hom.: 2 Cov.: 31 AF XY: 0.00148 AC XY: 1048 AN XY: 709606

Gnomad4 AFR exome AF: 0.000304

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.00117

Gnomad4 EAS exome AF: 0.0000262

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000212

Gnomad4 NFE exome AF: 0.00183

Gnomad4 OTH exome AF: 0.00145

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.00174 AC XY: 130 AN XY: 74510

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000658

Gnomad4 NFE AF: 0.00171

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000482 Hom.: 0

Bravo AF: 0.00188

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000729 AC: 3

ESP6500EA AF: 0.00155 AC: 13

ExAC AF: 0.000835 AC: 99

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6 Uncertain:1 Other:1

-

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 05-31-2019 by Sema4. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Philip Payne PhD, FACMI from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Jan 18, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified Benign:1

Jan 10, 2024

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CACNA1H-related disorder Benign:1

Apr 11, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1H: BS1, BS2 -

Epilepsy, idiopathic generalized, susceptibility to, 6 Other:1

Dec 01, 2007

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;D;.
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.2	L;.;L;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N;.;N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.55	T;.;T;T
Sift4G	Benign	0.17	T;.;T;T
Polyphen		0.89	P;.;D;D
Vest4		0.35
MVP		0.99
ClinPred		0.036	T
GERP RS		2.9
Varity_R		0.11
gMVP		0.61

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: rs58173258; hg19: chr16-1256126;