16-1219006-C-T

Variant names:

• chr16-1219006-C-T
• rs186422070
• NM_021098.3:c.5924C>T

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.5924C>T​(p.Ser1975Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000202 in 1,550,324 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1975S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.902
• 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018131495).
• BP6: Variant 16-1219006-C-T is Benign according to our data. Variant chr16-1219006-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460156.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000749 (114/152298) while in subpopulation AFR AF = 0.00255 (106/41556). AF 95% confidence interval is 0.00216. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 114 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.5924C>T	p.Ser1975Phe	missense	Exon 34 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.5906C>T	p.Ser1969Phe	missense	Exon 33 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.5924C>T	p.Ser1975Phe	missense	Exon 34 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.5939C>T	p.Ser1980Phe	missense	Exon 33 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.5909C>T	p.Ser1970Phe	missense	Exon 33 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152180 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000168 AC: 26 AN: 154606 AF XY: 0.000170

Gnomad AFR exome AF: 0.00270

Gnomad AMR exome AF: 0.0000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000672

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000142 AC: 199 AN: 1398026 Hom.: 1 Cov.: 33 AF XY: 0.000116 AC XY: 80 AN XY: 689542

African (AFR) AF: 0.00301 AC: 95 AN: 31596

American (AMR) AF: 0.0000280 AC: 1 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48050

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5680

European-Non Finnish (NFE) AF: 0.0000834 AC: 90 AN: 1078882

Other (OTH) AF: 0.000190 AC: 11 AN: 57994

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152298 Hom.: 0 Cov.: 31 AF XY: 0.000752 AC XY: 56 AN XY: 74470

African (AFR) AF: 0.00255 AC: 106 AN: 41556

American (AMR) AF: 0.000261 AC: 4 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

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

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: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000579 Hom.: 0

Bravo AF: 0.000922

ESP6500AA AF: 0.00233 AC: 8

ESP6500EA AF: 0.000147 AC: 1

ExAC AF: 0.000185 AC: 8

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.2	L
PhyloP100		0.90
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.35
Sift	Benign	0.11	T
Sift4G	Benign	0.15	T
Polyphen		0.68	P
Vest4		0.22
MVP		0.93
ClinPred		0.065	T
GERP RS		3.5
Varity_R		0.15
gMVP		0.30
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs186422070; hg19: chr16-1269006;