rs60593994

Variant names:

• chr16-1195509-G-C
• rs60593994
• NM_021098.3:c.489G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-1195509-G-C
• chr16-1195509-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.489G>C​(p.Gln163His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,602,790 control chromosomes in the GnomAD database, including 57 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. Q163P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (52 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.63
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009828389).
• BP6: Variant 16-1195509-G-C is Benign according to our data. Variant chr16-1195509-G-C is described in ClinVar as Benign. ClinVar VariationId is 460131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00363 (552/152246) while in subpopulation SAS AF = 0.0162 (78/4826). AF 95% confidence interval is 0.0133. There are 5 homozygotes in GnomAd4. There are 302 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 552 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.489G>C	p.Gln163His	missense_variant	Exon 4 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.489G>C	p.Gln163His	missense_variant	Exon 4 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.489G>C	p.Gln163His	missense_variant	Exon 4 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.489G>C	p.Gln163His	missense_variant	Exon 4 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.489G>C	p.Gln163His	missense_variant	Exon 4 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.489G>C	p.Gln163His	missense_variant	Exon 4 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.489G>C	p.Gln163His	missense_variant	Exon 4 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.450G>C	p.Gln150His	missense_variant	Exon 4 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.489G>C	p.Gln163His	missense_variant	Exon 4 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.450G>C	p.Gln150His	missense_variant	Exon 4 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.489G>C	p.Gln163His	missense_variant	Exon 4 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.489G>C	p.Gln163His	missense_variant	Exon 4 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.489G>C	p.Gln163His	missense_variant	Exon 4 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.489G>C	p.Gln163His	missense_variant	Exon 4 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.489G>C	p.Gln163His	missense_variant	Exon 4 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.489G>C		non_coding_transcript_exon_variant	Exon 4 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes AF: 0.00364 AC: 553 AN: 152128 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00490 AC: 1126 AN: 229966 AF XY: 0.00593

Gnomad AFR exome AF: 0.000583

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.00446

Gnomad EAS exome AF: 0.0000595

Gnomad FIN exome AF: 0.00547

Gnomad NFE exome AF: 0.00378

Gnomad OTH exome AF: 0.00610

GnomAD4 exome AF: 0.00406 AC: 5888 AN: 1450544 Hom.: 52 Cov.: 34 AF XY: 0.00453 AC XY: 3266 AN XY: 720216

African (AFR) AF: 0.000781 AC: 26 AN: 33312

American (AMR) AF: 0.00241 AC: 104 AN: 43160

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 119 AN: 25910

East Asian (EAS) AF: 0.0000510 AC: 2 AN: 39228

South Asian (SAS) AF: 0.0170 AC: 1428 AN: 83762

European-Finnish (FIN) AF: 0.00523 AC: 275 AN: 52534

Middle Eastern (MID) AF: 0.0208 AC: 119 AN: 5710

European-Non Finnish (NFE) AF: 0.00319 AC: 3529 AN: 1106930

Other (OTH) AF: 0.00477 AC: 286 AN: 59998

GnomAD4 genome AF: 0.00363 AC: 552 AN: 152246 Hom.: 5 Cov.: 33 AF XY: 0.00406 AC XY: 302 AN XY: 74450

African (AFR) AF: 0.000578 AC: 24 AN: 41548

American (AMR) AF: 0.00294 AC: 45 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4826

European-Finnish (FIN) AF: 0.00763 AC: 81 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00427 AC: 290 AN: 67988

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00471 Hom.: 3

Bravo AF: 0.00264

ESP6500AA AF: 0.000492 AC: 2

ESP6500EA AF: 0.00228 AC: 19

ExAC AF: 0.00472 AC: 569

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Jul 17, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30686625, 32227660) -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 05, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epilepsy, childhood absence, susceptibility to, 6 Benign:1

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Jan 20, 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	0.28
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.;.
Eigen	Benign	-0.093
Eigen_PC	Benign	-0.034
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.87	D;D;D;.
MetaRNN	Benign	0.0098	T;T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.76	N;.;N;N
PhyloP100		1.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N;.;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.061	T;.;T;T
Sift4G	Uncertain	0.028	D;.;D;D
Polyphen		0.051	B;.;D;D
Vest4		0.49
MutPred		0.49		Loss of helix (P = 0.028);.;Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.91
ClinPred		0.012	T
GERP RS		2.7
Varity_R		0.33
gMVP		0.61
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs60593994; hg19: chr16-1245509; COSMIC: COSV61989280;