16-1220372-C-T

Variant names:

• chr16-1220372-C-T
• rs748980218
• NM_021098.3:c.6440C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_021098.3(CACNA1H):​c.6440C>T​(p.Pro2147Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 1,522,246 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P2147Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.44
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000118 (18/152194) while in subpopulation AMR AF = 0.000785 (12/15290). AF 95% confidence interval is 0.000452. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 18 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.6440C>T	p.Pro2147Leu	missense	Exon 35 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.6422C>T	p.Pro2141Leu	missense	Exon 34 of 34	NP_001005407.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.6440C>T	p.Pro2147Leu	missense	Exon 35 of 35	ENSP00000334198.7
	CACNA1H	ENST00000569107.6	TSL:1	c.6455C>T	p.Pro2152Leu	missense	Exon 34 of 34	ENSP00000454990.2
	CACNA1H	ENST00000711493.1		c.6425C>T	p.Pro2142Leu	missense	Exon 34 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

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: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000522 AC: 8 AN: 153156 AF XY: 0.0000349

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: 0.0000828

Gnomad NFE exome AF: 0.0000812

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000482 AC: 66 AN: 1370052 Hom.: 0 Cov.: 35 AF XY: 0.0000429 AC XY: 29 AN XY: 675736

African (AFR) AF: 0.00 AC: 0 AN: 28860

American (AMR) AF: 0.0000665 AC: 2 AN: 30078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20742

East Asian (EAS) AF: 0.00 AC: 0 AN: 37140

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73364

European-Finnish (FIN) AF: 0.000117 AC: 5 AN: 42614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5348

European-Non Finnish (NFE) AF: 0.0000530 AC: 57 AN: 1075492

Other (OTH) AF: 0.0000177 AC: 1 AN: 56414

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74354

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.000785 AC: 12 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68016

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000170

ExAC AF: 0.0000877 AC: 10

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	0.023
Eigen_PC	Benign	-0.036
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		2.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.45	B
Vest4		0.23
MutPred		0.30		Loss of ubiquitination at K2146 (P = 0.0369)
MVP		0.95
ClinPred		0.49	T
GERP RS		4.4
Varity_R		0.24
gMVP		0.26
Mutation Taster		=66/34	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: rs748980218; hg19: chr16-1270372;