16-1208220-C-T

Variant names:

• chr16-1208220-C-T
• rs200832286
• NM_021098.3:c.3362C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.3362C>T​(p.Pro1121Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,555,508 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1121R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: CACNA1H NM_021098.3 missense, splice_region
• Scores: Splicing: ADA: 0.0006344
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.347
• 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: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013791889).
• BP6: Variant 16-1208220-C-T is Benign according to our data. Variant chr16-1208220-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 460085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000565 (86/152288) while in subpopulation SAS AF = 0.00145 (7/4824). AF 95% confidence interval is 0.000894. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 86 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.3362C>T	p.Pro1121Leu	missense splice_region	Exon 16 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.3362C>T	p.Pro1121Leu	missense splice_region	Exon 16 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.3362C>T	p.Pro1121Leu	missense splice_region	Exon 16 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.3362C>T	p.Pro1121Leu	missense splice_region	Exon 16 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.3362C>T	p.Pro1121Leu	missense splice_region	Exon 16 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000349 AC: 56 AN: 160476 AF XY: 0.000414

Gnomad AFR exome AF: 0.000723

Gnomad AMR exome AF: 0.000460

Gnomad ASJ exome AF: 0.000116

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000154

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000393 AC: 551 AN: 1403220 Hom.: 1 Cov.: 32 AF XY: 0.000438 AC XY: 304 AN XY: 693866

African (AFR) AF: 0.00116 AC: 37 AN: 31874

American (AMR) AF: 0.000400 AC: 15 AN: 37526

Ashkenazi Jewish (ASJ) AF: 0.0000395 AC: 1 AN: 25292

East Asian (EAS) AF: 0.00 AC: 0 AN: 36412

South Asian (SAS) AF: 0.00128 AC: 102 AN: 79834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45356

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4138

European-Non Finnish (NFE) AF: 0.000345 AC: 374 AN: 1084546

Other (OTH) AF: 0.000275 AC: 16 AN: 58242

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74470

African (AFR) AF: 0.00115 AC: 48 AN: 41566

American (AMR) AF: 0.000523 AC: 8 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000350 Hom.: 0

Bravo AF: 0.000487

ESP6500AA AF: 0.000544 AC: 2

ESP6500EA AF: 0.000124 AC: 1

ExAC AF: 0.000235 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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	0.064
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.68
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	-0.51	N
PhyloP100		0.35
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.28
Sift	Benign	0.54	T
Sift4G	Benign	0.57	T
Polyphen		0.0010	B
Vest4		0.12
MVP		0.37
ClinPred		0.0022	T
GERP RS		2.7
Varity_R		0.040
gMVP		0.25
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00063
dbscSNV1_RF	Benign	0.13
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: rs200832286; hg19: chr16-1258220; COSMIC: COSV100670397; COSMIC: COSV100670397;