rs538923520

Variant names:

• chr16-1204160-A-C
• rs538923520
• NM_021098.3:c.2153A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-1204160-A-C
• chr16-1204160-A-G

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.2153A>C​(p.Glu718Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000486 in 1,612,288 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E718Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (14 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.94
• Publications: 1 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=0.007634878).
• BP6: Variant 16-1204160-A-C is Benign according to our data. Variant chr16-1204160-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 529632.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 = 0.000263 (40/152328) while in subpopulation SAS AF = 0.00807 (39/4830). AF 95% confidence interval is 0.00607. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 40 AD gene.

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.2153A>C	p.Glu718Ala	missense	Exon 10 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.2153A>C	p.Glu718Ala	missense	Exon 10 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.2153A>C	p.Glu718Ala	missense	Exon 10 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.2153A>C	p.Glu718Ala	missense	Exon 10 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.2153A>C	p.Glu718Ala	missense	Exon 10 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152210 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000980 AC: 240 AN: 244980 AF XY: 0.00134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000510 AC: 744 AN: 1459960 Hom.: 14 Cov.: 32 AF XY: 0.000778 AC XY: 565 AN XY: 726258

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00829 AC: 715 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51998

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111692

Other (OTH) AF: 0.000298 AC: 18 AN: 60308

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00807 AC: 39 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000419 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.00107 AC: 129

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.047
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0076	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.9
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.30
Sift	Benign	0.034	D
Sift4G	Uncertain	0.044	D
Polyphen		0.80	P
Vest4		0.30
MutPred		0.27		Loss of solvent accessibility (P = 0.0576)
MVP		0.86
ClinPred		0.14	T
GERP RS		4.0
Varity_R		0.23
gMVP		0.39
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs538923520; hg19: chr16-1254160;