chr16-1214973-C-T

Variant names:

• chr16-1214973-C-T
• rs745902196
• NM_021098.3:c.4931C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_021098.3(CACNA1H):​c.4931C>T​(p.Ser1644Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000689 in 1,450,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S1644S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense, splice_region
• Scores: Splicing: ADA: 0.001640
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.12
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25662166).
• BS2: High AC in GnomAdExome4 at 10 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.4931C>T	p.Ser1644Leu	missense splice_region	Exon 28 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.4913C>T	p.Ser1638Leu	missense splice_region	Exon 27 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.4931C>T	p.Ser1644Leu	missense splice_region	Exon 28 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.4946C>T	p.Ser1649Leu	missense splice_region	Exon 27 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.4949C>T	p.Ser1650Leu	missense splice_region	Exon 27 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000860 AC: 2 AN: 232614 AF XY: 0.0000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000486

Gnomad NFE exome AF: 0.00000954

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000689 AC: 10 AN: 1450418 Hom.: 0 Cov.: 32 AF XY: 0.00000555 AC XY: 4 AN XY: 720462

African (AFR) AF: 0.00 AC: 0 AN: 33258

American (AMR) AF: 0.00 AC: 0 AN: 43324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25842

East Asian (EAS) AF: 0.00 AC: 0 AN: 39316

South Asian (SAS) AF: 0.00 AC: 0 AN: 84338

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000814 AC: 9 AN: 1106304

Other (OTH) AF: 0.00 AC: 0 AN: 59988

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000830 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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	0.12
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Benign	0.88
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	0.098
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.26	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.48
Sift	Benign	0.76	T
Sift4G	Benign	0.72	T
Polyphen		0.061	B
Vest4		0.62
MutPred		0.55		Loss of disorder (P = 0.0071)
MVP		0.87
ClinPred		0.39	T
GERP RS		4.3
Varity_R		0.28
gMVP		0.62
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.038
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: rs745902196; hg19: chr16-1264973; COSMIC: COSV61989541; COSMIC: COSV61989541;