rs370883583

Variant names:

• chr16-1220131-G-A
• rs370883583
• NM_021098.3:c.6199G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_021098.3(CACNA1H):​c.6199G>A​(p.Val2067Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,495,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2067A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -3.85
• 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: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028915316).
• BP6: Variant 16-1220131-G-A is Benign according to our data. Variant chr16-1220131-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529574.
• BS2: High AC in GnomAd4 at 12 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.6199G>A	p.Val2067Ile	missense	Exon 35 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.6181G>A	p.Val2061Ile	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.6199G>A	p.Val2067Ile	missense	Exon 35 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.6214G>A	p.Val2072Ile	missense	Exon 34 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.6184G>A	p.Val2062Ile	missense	Exon 34 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152184 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000680 AC: 10 AN: 147110 AF XY: 0.0000618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000978

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000142 AC: 191 AN: 1343102 Hom.: 0 Cov.: 31 AF XY: 0.000131 AC XY: 86 AN XY: 658236

African (AFR) AF: 0.0000366 AC: 1 AN: 27336

American (AMR) AF: 0.00 AC: 0 AN: 29936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20400

East Asian (EAS) AF: 0.0000886 AC: 3 AN: 33844

South Asian (SAS) AF: 0.00 AC: 0 AN: 66664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48508

Middle Eastern (MID) AF: 0.000187 AC: 1 AN: 5336

European-Non Finnish (NFE) AF: 0.000166 AC: 175 AN: 1055804

Other (OTH) AF: 0.000199 AC: 11 AN: 55274

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152302 Hom.: 0 Cov.: 35 AF XY: 0.0000537 AC XY: 4 AN XY: 74466

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.0000586 AC: 7

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV (1)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.017
DANN	Benign	0.89
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.029	T
MetaSVM	Uncertain	0.046	D
MutationAssessor	Benign	0.62	N
PhyloP100		-3.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.21
Sift	Benign	0.48	T
Sift4G	Benign	0.26	T
Polyphen		0.0030	B
Vest4		0.027
MVP		0.61
ClinPred		0.038	T
GERP RS		-8.3
Varity_R		0.042
gMVP		0.14
Mutation Taster		=91/9	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: rs370883583; hg19: chr16-1270131; COSMIC: COSV52352781; COSMIC: COSV52352781;