rs28365124

Variant names:

• chr16-1210636-G-A
• rs28365124
• NM_021098.3:c.4023G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021098.3(CACNA1H):​c.4023G>A​(p.Ala1341Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0593 in 1,605,038 control chromosomes in the GnomAD database, including 3,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (249 hom., cov: 33)
  • Exomes 𝑓: 0.061 (3083 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.34
• 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-1210636-G-A is Benign according to our data. Variant chr16-1210636-G-A is described in ClinVar as Benign. ClinVar VariationId is 585639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4023G>A	p.Ala1341Ala	synonymous_variant	Exon 20 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4023G>A	p.Ala1341Ala	synonymous_variant	Exon 20 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.4023G>A	p.Ala1341Ala	synonymous_variant	Exon 20 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.4023G>A	p.Ala1341Ala	synonymous_variant	Exon 20 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.4023G>A	p.Ala1341Ala	synonymous_variant	Exon 20 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.4023G>A	p.Ala1341Ala	synonymous_variant	Exon 20 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.4023G>A	p.Ala1341Ala	synonymous_variant	Exon 20 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.3984G>A	p.Ala1328Ala	synonymous_variant	Exon 20 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.4023G>A	p.Ala1341Ala	synonymous_variant	Exon 20 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.3984G>A	p.Ala1328Ala	synonymous_variant	Exon 20 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.4023G>A	p.Ala1341Ala	synonymous_variant	Exon 20 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.4023G>A	p.Ala1341Ala	synonymous_variant	Exon 20 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.4023G>A	p.Ala1341Ala	synonymous_variant	Exon 20 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.4023G>A	p.Ala1341Ala	synonymous_variant	Exon 20 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.4023G>A	p.Ala1341Ala	synonymous_variant	Exon 20 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.4023G>A		non_coding_transcript_exon_variant	Exon 20 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.4073G>A		non_coding_transcript_exon_variant	Exon 20 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.4023G>A		non_coding_transcript_exon_variant	Exon 20 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1936G>A		non_coding_transcript_exon_variant	Exon 20 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*3470G>A		non_coding_transcript_exon_variant	Exon 19 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.4023G>A		non_coding_transcript_exon_variant	Exon 20 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.4023G>A		non_coding_transcript_exon_variant	Exon 20 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.4023G>A		non_coding_transcript_exon_variant	Exon 20 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.4023G>A		non_coding_transcript_exon_variant	Exon 20 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.4023G>A		non_coding_transcript_exon_variant	Exon 20 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.4023G>A		non_coding_transcript_exon_variant	Exon 20 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.4023G>A		non_coding_transcript_exon_variant	Exon 20 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.4023G>A		non_coding_transcript_exon_variant	Exon 20 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.4023G>A		non_coding_transcript_exon_variant	Exon 20 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1	n.*1936G>A		3_prime_UTR_variant	Exon 20 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*3470G>A		3_prime_UTR_variant	Exon 19 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 7160 AN: 152140 Hom.: 248 Cov.: 33

Gnomad AFR AF: 0.00948

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0435

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0828

Gnomad FIN AF: 0.0498

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0669

Gnomad OTH AF: 0.0569

GnomAD2 exomes AF: 0.0553 AC: 13321 AN: 241058 AF XY: 0.0592

Gnomad AFR exome AF: 0.00881

Gnomad AMR exome AF: 0.0315

Gnomad ASJ exome AF: 0.0925

Gnomad EAS exome AF: 0.000393

Gnomad FIN exome AF: 0.0520

Gnomad NFE exome AF: 0.0653

Gnomad OTH exome AF: 0.0663

GnomAD4 exome AF: 0.0606 AC: 87993 AN: 1452780 Hom.: 3083 Cov.: 40 AF XY: 0.0618 AC XY: 44693 AN XY: 722948

African (AFR) AF: 0.00854 AC: 286 AN: 33472

American (AMR) AF: 0.0323 AC: 1443 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0936 AC: 2444 AN: 26120

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39688

South Asian (SAS) AF: 0.0865 AC: 7455 AN: 86198

European-Finnish (FIN) AF: 0.0520 AC: 2339 AN: 44962

Middle Eastern (MID) AF: 0.0841 AC: 485 AN: 5766

European-Non Finnish (NFE) AF: 0.0629 AC: 69871 AN: 1111616

Other (OTH) AF: 0.0607 AC: 3659 AN: 60282

GnomAD4 genome AF: 0.0470 AC: 7161 AN: 152258 Hom.: 249 Cov.: 33 AF XY: 0.0457 AC XY: 3405 AN XY: 74458

African (AFR) AF: 0.00946 AC: 393 AN: 41558

American (AMR) AF: 0.0435 AC: 665 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0916 AC: 318 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5182

South Asian (SAS) AF: 0.0833 AC: 402 AN: 4828

European-Finnish (FIN) AF: 0.0498 AC: 528 AN: 10610

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0669 AC: 4550 AN: 67988

Other (OTH) AF: 0.0558 AC: 118 AN: 2114

Alfa AF: 0.0646 Hom.: 101

Bravo AF: 0.0419

Asia WGS AF: 0.0310 AC: 108 AN: 3478

EpiCase AF: 0.0710

EpiControl AF: 0.0722

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.7
DANN	Benign	0.93
PhyloP100		-2.3
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs28365124; hg19: chr16-1260636;