chr16-1219003-A-G

Variant names:

• chr16-1219003-A-G
• rs3751886
• NM_021098.3:c.5921A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_021098.3(CACNA1H):​c.5921A>G​(p.Glu1974Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0278 in 1,550,202 control chromosomes in the GnomAD database, including 1,192 homozygotes. 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. E1974K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.052 (408 hom., cov: 31)
  • Exomes 𝑓: 0.025 (784 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.692
• Publications: 14 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 -16 ACMG points.

• BP6: Variant 16-1219003-A-G is Benign according to our data. Variant chr16-1219003-A-G is described in ClinVar as Benign. ClinVar VariationId is 446956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.5921A>G	p.Glu1974Gly	missense	Exon 34 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.5903A>G	p.Glu1968Gly	missense	Exon 33 of 34	NP_001005407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.5921A>G	p.Glu1974Gly	missense	Exon 34 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.5936A>G	p.Glu1979Gly	missense	Exon 33 of 34	ENSP00000454990.2
	CACNA1H	ENST00000565831.7	TSL:1	c.5903A>G	p.Glu1968Gly	missense	Exon 33 of 34	ENSP00000455840.1

Frequencies

GnomAD3 genomes AF: 0.0515 AC: 7832 AN: 152066 Hom.: 398 Cov.: 31

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0349

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.0964

Gnomad SAS AF: 0.0422

Gnomad FIN AF: 0.00790

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0435

GnomAD2 exomes AF: 0.0345 AC: 5338 AN: 154678 AF XY: 0.0332

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.0454

Gnomad ASJ exome AF: 0.00684

Gnomad EAS exome AF: 0.0858

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0236

GnomAD4 exome AF: 0.0252 AC: 35188 AN: 1398018 Hom.: 784 Cov.: 33 AF XY: 0.0250 AC XY: 17270 AN XY: 689532

African (AFR) AF: 0.132 AC: 4164 AN: 31594

American (AMR) AF: 0.0444 AC: 1584 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.00648 AC: 163 AN: 25162

East Asian (EAS) AF: 0.0803 AC: 2870 AN: 35732

South Asian (SAS) AF: 0.0377 AC: 2983 AN: 79228

European-Finnish (FIN) AF: 0.0105 AC: 505 AN: 48062

Middle Eastern (MID) AF: 0.0232 AC: 132 AN: 5678

European-Non Finnish (NFE) AF: 0.0193 AC: 20867 AN: 1078878

Other (OTH) AF: 0.0331 AC: 1920 AN: 57994

GnomAD4 genome AF: 0.0517 AC: 7866 AN: 152184 Hom.: 408 Cov.: 31 AF XY: 0.0508 AC XY: 3783 AN XY: 74426

African (AFR) AF: 0.125 AC: 5196 AN: 41478

American (AMR) AF: 0.0349 AC: 534 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.0968 AC: 499 AN: 5154

South Asian (SAS) AF: 0.0420 AC: 203 AN: 4832

European-Finnish (FIN) AF: 0.00790 AC: 84 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0181 AC: 1230 AN: 67998

Other (OTH) AF: 0.0426 AC: 90 AN: 2112

Alfa AF: 0.0246 Hom.: 185

Bravo AF: 0.0567

TwinsUK AF: 0.0221 AC: 82

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.0999 AC: 341

ESP6500EA AF: 0.0150 AC: 102

ExAC AF: 0.0216 AC: 919

Asia WGS AF: 0.0780 AC: 269 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 27, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jun 26, 2017

Athena Diagnostics

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.77	T
PhyloP100		0.69
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.18
Sift	Benign	0.050	D
Sift4G	Benign	0.23	T
Polyphen		0.0010	B
Vest4		0.17
ClinPred		0.010	T
GERP RS		2.1
Varity_R		0.096
gMVP		0.33
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3751886; hg19: chr16-1269003; COSMIC: COSV52352515; COSMIC: COSV52352515;