chr16-1201967-G-A

Variant names:

• chr16-1201967-G-A
• rs532223684
• NM_021098.3:c.1517G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.1517G>A​(p.Arg506Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,544,256 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. R506G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.89
• Publications: 2 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022917151).
• BP6: Variant 16-1201967-G-A is Benign according to our data. Variant chr16-1201967-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529607.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000243 (37/152260) while in subpopulation AMR AF = 0.00131 (20/15310). AF 95% confidence interval is 0.000865. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 37 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.1517G>A	p.Arg506Gln	missense	Exon 9 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.1517G>A	p.Arg506Gln	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.1517G>A	p.Arg506Gln	missense	Exon 9 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.1517G>A	p.Arg506Gln	missense	Exon 9 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.1517G>A	p.Arg506Gln	missense	Exon 9 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152142 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000206 AC: 29 AN: 140622 AF XY: 0.000211

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.000246

Gnomad ASJ exome AF: 0.000734

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000214

Gnomad OTH exome AF: 0.000480

GnomAD4 exome AF: 0.000141 AC: 196 AN: 1391996 Hom.: 0 Cov.: 36 AF XY: 0.000136 AC XY: 93 AN XY: 685902

African (AFR) AF: 0.0000635 AC: 2 AN: 31490

American (AMR) AF: 0.000422 AC: 15 AN: 35582

Ashkenazi Jewish (ASJ) AF: 0.000717 AC: 18 AN: 25088

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35616

South Asian (SAS) AF: 0.000202 AC: 16 AN: 79112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5584

European-Non Finnish (NFE) AF: 0.000115 AC: 124 AN: 1076306

Other (OTH) AF: 0.000346 AC: 20 AN: 57798

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152260 Hom.: 0 Cov.: 34 AF XY: 0.000282 AC XY: 21 AN XY: 74456

African (AFR) AF: 0.0000241 AC: 1 AN: 41548

American (AMR) AF: 0.00131 AC: 20 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67994

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000264

ExAC AF: 0.000110 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	15
DANN	Benign	0.72
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	0.019	D
MutationAssessor	Benign	1.7	L
PhyloP100		1.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.23
Sift	Benign	0.59	T
Sift4G	Benign	0.22	T
Polyphen		0.0070	B
Vest4		0.096
MutPred		0.38		Loss of MoRF binding (P = 0.0846)
MVP		0.76
ClinPred		0.012	T
GERP RS		2.9
Varity_R		0.085
gMVP		0.32
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: rs532223684; hg19: chr16-1251967; COSMIC: COSV104661970; COSMIC: COSV104661970;