rs56930660

Variant names:

• chr16-1220254-G-A
• rs56930660
• NM_021098.3:c.6322G>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.6322G>A​(p.Ala2108Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,583,922 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 35)
  • Exomes 𝑓: 0.0019 (7 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.77

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=0.03981313).
• BP6: Variant 16-1220254-G-A is Benign according to our data. Variant chr16-1220254-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 460163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1220254-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00123 (187/152212) while in subpopulation NFE AF= 0.00204 (139/68000). AF 95% confidence interval is 0.00177. There are 1 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 187 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6322G>A	p.Ala2108Thr	missense_variant	Exon 35 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6322G>A	p.Ala2108Thr	missense_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.6304G>A	p.Ala2102Thr	missense_variant	Exon 33 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.6283G>A	p.Ala2095Thr	missense_variant	Exon 35 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.2560G>A	p.Ala854Thr	missense_variant	Exon 17 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.2512G>A	p.Ala838Thr	missense_variant	Exon 18 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.2494G>A	p.Ala832Thr	missense_variant	Exon 17 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*1370G>A		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4140G>A		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*1370G>A		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4140G>A		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152098 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000591

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00145 AC: 301 AN: 208054 Hom.: 2 AF XY: 0.00148 AC XY: 173 AN XY: 117236

Gnomad AFR exome AF: 0.000285

Gnomad AMR exome AF: 0.000555

Gnomad ASJ exome AF: 0.00125

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00116

Gnomad FIN exome AF: 0.000489

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.00193 AC: 2760 AN: 1431710 Hom.: 7 Cov.: 73 AF XY: 0.00193 AC XY: 1377 AN XY: 711966

Gnomad4 AFR exome AF: 0.000352

Gnomad4 AMR exome AF: 0.000464

Gnomad4 ASJ exome AF: 0.00114

Gnomad4 EAS exome AF: 0.0000264

Gnomad4 SAS exome AF: 0.000890

Gnomad4 FIN exome AF: 0.000757

Gnomad4 NFE exome AF: 0.00226

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152212 Hom.: 1 Cov.: 35 AF XY: 0.00114 AC XY: 85 AN XY: 74416

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000591

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.00122

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00169 AC: 12

ExAC AF: 0.00128 AC: 149

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1H: BS2 -

Apr 08, 2019

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CACNA1H-related disorder Benign:1

Jun 29, 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). -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Oct 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T;T;T;.
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.040	T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.59	N;.;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.31	T;.;T;T
Sift4G	Benign	0.61	T;.;T;T
Polyphen		0.99	D;.;P;P
Vest4		0.076
MVP		0.93
ClinPred		0.022	T
GERP RS		4.3
Varity_R		0.057
gMVP		0.24

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: rs56930660; hg19: chr16-1270254;