rs4984636

Variant names:

• chr16-1202441-T-C
• rs4984636
• NM_021098.3:c.1991T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-1202441-T-C
• chr16-1202441-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021098.3(CACNA1H):​c.1991T>C​(p.Val664Ala) variant causes a missense change. The variant allele was found at a frequency of 0.272 in 1,494,282 control chromosomes in the GnomAD database, including 61,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V664G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.20 (4069 hom., cov: 33)
  • Exomes 𝑓: 0.28 (57732 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.18
• Publications: 35 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=0.0039284825).
• BP6: Variant 16-1202441-T-C is Benign according to our data. Variant chr16-1202441-T-C is described in ClinVar as Benign. ClinVar VariationId is 96006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.295 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.1991T>C	p.Val664Ala	missense	Exon 9 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.1991T>C	p.Val664Ala	missense	Exon 9 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.1991T>C	p.Val664Ala	missense	Exon 9 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.1991T>C	p.Val664Ala	missense	Exon 9 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.1991T>C	p.Val664Ala	missense	Exon 9 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30186 AN: 151904 Hom.: 4069 Cov.: 33

Gnomad AFR AF: 0.0557

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.00348

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.175

GnomAD2 exomes AF: 0.194 AC: 21076 AN: 108804 AF XY: 0.195

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.00146

Gnomad FIN exome AF: 0.343

Gnomad NFE exome AF: 0.297

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.280 AC: 375807 AN: 1342260 Hom.: 57732 Cov.: 38 AF XY: 0.275 AC XY: 180417 AN XY: 654884

African (AFR) AF: 0.0404 AC: 1235 AN: 30554

American (AMR) AF: 0.152 AC: 4843 AN: 31878

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 2914 AN: 22264

East Asian (EAS) AF: 0.00456 AC: 160 AN: 35114

South Asian (SAS) AF: 0.125 AC: 9004 AN: 71892

European-Finnish (FIN) AF: 0.322 AC: 12914 AN: 40152

Middle Eastern (MID) AF: 0.120 AC: 654 AN: 5444

European-Non Finnish (NFE) AF: 0.316 AC: 331199 AN: 1049348

Other (OTH) AF: 0.232 AC: 12884 AN: 55614

GnomAD4 genome AF: 0.199 AC: 30184 AN: 152022 Hom.: 4069 Cov.: 33 AF XY: 0.196 AC XY: 14533 AN XY: 74310

African (AFR) AF: 0.0555 AC: 2304 AN: 41480

American (AMR) AF: 0.162 AC: 2478 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 465 AN: 3472

East Asian (EAS) AF: 0.00349 AC: 18 AN: 5156

South Asian (SAS) AF: 0.117 AC: 563 AN: 4810

European-Finnish (FIN) AF: 0.319 AC: 3378 AN: 10584

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.299 AC: 20282 AN: 67914

Other (OTH) AF: 0.173 AC: 365 AN: 2110

Alfa AF: 0.245 Hom.: 11666

Bravo AF: 0.183

TwinsUK AF: 0.325 AC: 1206

ALSPAC AF: 0.321 AC: 1239

ESP6500AA AF: 0.0488 AC: 178

ESP6500EA AF: 0.244 AC: 1823

ExAC AF: 0.111 AC: 8140

Asia WGS AF: 0.0510 AC: 179 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.011	D
Sift4G	Benign	0.25	T
Polyphen		0.96	D
Vest4		0.44
ClinPred		0.013	T
GERP RS		4.5
Varity_R		0.32
gMVP		0.35
Mutation Taster		=99/1	polymorphism (auto)

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: rs4984636; hg19: chr16-1252441; COSMIC: COSV61983157; COSMIC: COSV61983157;