rs36117280

Variant names:

• chr16-1200389-A-G
• rs36117280
• NM_021098.3:c.937A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-1200389-A-G
• chr16-1200389-A-T

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.937A>G​(p.Met313Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,605,316 control chromosomes in the GnomAD database, including 18,100 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1408 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16692 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.365
• Publications: 19 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: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017673373).
• BP6: Variant 16-1200389-A-G is Benign according to our data. Variant chr16-1200389-A-G is described in ClinVar as Benign. ClinVar VariationId is 585657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.154 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.937A>G	p.Met313Val	missense	Exon 7 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.937A>G	p.Met313Val	missense	Exon 7 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.937A>G	p.Met313Val	missense	Exon 7 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.937A>G	p.Met313Val	missense	Exon 7 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.937A>G	p.Met313Val	missense	Exon 7 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19440 AN: 152186 Hom.: 1404 Cov.: 32

Gnomad AFR AF: 0.0847

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.0649

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.133 AC: 31097 AN: 233864 AF XY: 0.140

Gnomad AFR exome AF: 0.0782

Gnomad AMR exome AF: 0.0667

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.0664

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.149 AC: 216241 AN: 1453012 Hom.: 16692 Cov.: 34 AF XY: 0.150 AC XY: 108507 AN XY: 722448

African (AFR) AF: 0.0787 AC: 2621 AN: 33314

American (AMR) AF: 0.0716 AC: 3141 AN: 43880

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3100 AN: 25982

East Asian (EAS) AF: 0.0434 AC: 1712 AN: 39426

South Asian (SAS) AF: 0.170 AC: 14531 AN: 85720

European-Finnish (FIN) AF: 0.164 AC: 8203 AN: 49996

Middle Eastern (MID) AF: 0.129 AC: 744 AN: 5762

European-Non Finnish (NFE) AF: 0.157 AC: 173675 AN: 1108840

Other (OTH) AF: 0.142 AC: 8514 AN: 60092

GnomAD4 genome AF: 0.128 AC: 19462 AN: 152304 Hom.: 1408 Cov.: 32 AF XY: 0.129 AC XY: 9610 AN XY: 74464

African (AFR) AF: 0.0852 AC: 3544 AN: 41578

American (AMR) AF: 0.107 AC: 1644 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 394 AN: 3472

East Asian (EAS) AF: 0.0644 AC: 334 AN: 5184

South Asian (SAS) AF: 0.163 AC: 786 AN: 4820

European-Finnish (FIN) AF: 0.172 AC: 1822 AN: 10616

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10547 AN: 68006

Other (OTH) AF: 0.137 AC: 289 AN: 2116

Alfa AF: 0.145 Hom.: 1612

Bravo AF: 0.120

TwinsUK AF: 0.149 AC: 553

ALSPAC AF: 0.154 AC: 593

ESP6500AA AF: 0.0705 AC: 286

ESP6500EA AF: 0.144 AC: 1201

ExAC AF: 0.133 AC: 15899

Asia WGS AF: 0.121 AC: 422 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	2.1
DANN	Benign	0.48
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.0082	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-0.60	N
PhyloP100		0.36
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.27
Sift	Benign	0.67	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.18
ClinPred		0.00026	T
GERP RS		1.3
Varity_R		0.040
gMVP		0.76
Mutation Taster		=100/0	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: rs36117280; hg19: chr16-1250389; COSMIC: COSV61993451; COSMIC: COSV61993451;