rs150601404

Variant names:

• chr16-1220989-G-A
• rs150601404
• NM_021098.3:c.7057G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1220989-G-A
• chr16-1220989-G-C
• chr16-1220989-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_021098.3(CACNA1H):​c.7057G>A​(p.Val2353Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,574,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. V2353E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.33
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017772585).
• BP6: Variant 16-1220989-G-A is Benign according to our data. Variant chr16-1220989-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 460185.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000401 (61/152290) while in subpopulation AFR AF = 0.0012 (50/41580). AF 95% confidence interval is 0.000937. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 61 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.7057G>A	p.Val2353Met	missense	Exon 35 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.7039G>A	p.Val2347Met	missense	Exon 34 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.7057G>A	p.Val2353Met	missense	Exon 35 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.7072G>A	p.Val2358Met	missense	Exon 34 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.7042G>A	p.Val2348Met	missense	Exon 34 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000116 AC: 24 AN: 206680 AF XY: 0.0000964

Gnomad AFR exome AF: 0.00113

Gnomad AMR exome AF: 0.000179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000426

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 175 AN: 1422112 Hom.: 0 Cov.: 34 AF XY: 0.000104 AC XY: 73 AN XY: 704428

African (AFR) AF: 0.00120 AC: 38 AN: 31634

American (AMR) AF: 0.000132 AC: 5 AN: 37990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23762

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39194

South Asian (SAS) AF: 0.0000371 AC: 3 AN: 80960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5404

European-Non Finnish (NFE) AF: 0.000111 AC: 122 AN: 1094278

Other (OTH) AF: 0.000103 AC: 6 AN: 58326

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74456

African (AFR) AF: 0.00120 AC: 50 AN: 41580

American (AMR) AF: 0.000261 AC: 4 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

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: 0.0000882 AC: 6 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.000359

ESP6500AA AF: 0.00110 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000142 AC: 17

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	0.058	D
MutationAssessor	Benign	0.97	L
PhyloP100		2.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.23
Sift	Benign	0.076	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.037	B
Vest4		0.29
MVP		0.78
ClinPred		0.013	T
GERP RS		1.9
Varity_R		0.055
gMVP		0.11
Mutation Taster		=97/3	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: rs150601404; hg19: chr16-1270989; COSMIC: COSV52354520; COSMIC: COSV52354520;