16-1153789-C-T

Variant names:

• chr16-1153789-C-T
• NM_021098.3:c.52C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021098.3(CACNA1H):​c.52C>T​(p.Pro18Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P18P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.218
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11987355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.52C>T	p.Pro18Ser	missense_variant	Exon 2 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.52C>T		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1078894 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 512108

African (AFR) AF: 0.00 AC: 0 AN: 22076

American (AMR) AF: 0.00 AC: 0 AN: 7690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13430

East Asian (EAS) AF: 0.00 AC: 0 AN: 24398

South Asian (SAS) AF: 0.00 AC: 0 AN: 25044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2834

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 918840

Other (OTH) AF: 0.00 AC: 0 AN: 42710

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.52C>T (p.P18S) alteration is located in exon 2 (coding exon 1) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 52, causing the proline (P) at amino acid position 18 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.12	T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.45	T;T;T;.
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.0	N;.;N;N
PhyloP100		-0.22
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.090	N;.;N;N
REVEL	Benign	0.27
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	0.78	T;.;T;T
Polyphen		0.0010	B;.;B;B
Vest4		0.17
MutPred		0.26		Loss of catalytic residue at P18 (P = 0.0057);Loss of catalytic residue at P18 (P = 0.0057);Loss of catalytic residue at P18 (P = 0.0057);Loss of catalytic residue at P18 (P = 0.0057);
MVP		0.42
ClinPred		0.030	T
GERP RS		0.52
PromoterAI		0.048	Neutral
Varity_R		0.026
gMVP		0.26
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr16-1203789;