chr16-1153778-C-T

Variant names:

• chr16-1153778-C-T
• rs1263557227
• NM_021098.3:c.41C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The NM_021098.3(CACNA1H):​c.41C>T​(p.Pro14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000619 in 1,226,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. P14S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.66
• 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: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.35292497).
• BP6: Variant 16-1153778-C-T is Benign according to our data. Variant chr16-1153778-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1475245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 72 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.41C>T	p.Pro14Leu	missense	Exon 2 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.41C>T	p.Pro14Leu	missense	Exon 2 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.41C>T	p.Pro14Leu	missense	Exon 2 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.41C>T	p.Pro14Leu	missense	Exon 2 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.41C>T	p.Pro14Leu	missense	Exon 2 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.0000265 AC: 4 AN: 150980 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000669 AC: 72 AN: 1075876 Hom.: 0 Cov.: 32 AF XY: 0.0000725 AC XY: 37 AN XY: 510422

African (AFR) AF: 0.00 AC: 0 AN: 21982

American (AMR) AF: 0.00 AC: 0 AN: 7622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13350

East Asian (EAS) AF: 0.00 AC: 0 AN: 24176

South Asian (SAS) AF: 0.000162 AC: 4 AN: 24658

European-Finnish (FIN) AF: 0.0000460 AC: 1 AN: 21752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2818

European-Non Finnish (NFE) AF: 0.0000687 AC: 63 AN: 916952

Other (OTH) AF: 0.0000940 AC: 4 AN: 42566

GnomAD4 genome AF: 0.0000265 AC: 4 AN: 150980 Hom.: 0 Cov.: 30 AF XY: 0.0000407 AC XY: 3 AN XY: 73714

African (AFR) AF: 0.00 AC: 0 AN: 41204

American (AMR) AF: 0.00 AC: 0 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5058

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67682

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.4	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.20
MutPred		0.30		Gain of helix (P = 0.005)
MVP		0.74
ClinPred		0.94	D
GERP RS		2.9
PromoterAI		-0.026	Neutral
Varity_R		0.22
gMVP		0.42
Mutation Taster		=92/8	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: rs1263557227; hg19: chr16-1203778;