chr16-1212030-G-T

Variant names:

• chr16-1212030-G-T
• rs369045626
• NM_021098.3:c.4651G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_021098.3(CACNA1H):​c.4651G>T​(p.Val1551Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1551M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.63
• 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_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_021098.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4651G>T	p.Val1551Leu	missense_variant	Exon 25 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4651G>T	p.Val1551Leu	missense_variant	Exon 25 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.4651G>T	p.Val1551Leu	missense_variant	Exon 25 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.4687G>T	p.Val1563Leu	missense_variant	Exon 25 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.4651G>T	p.Val1551Leu	missense_variant	Exon 25 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.4589G>T	p.Arg1530Leu	missense_variant	Exon 25 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.4651G>T	p.Val1551Leu	missense_variant	Exon 25 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.4612G>T	p.Val1538Leu	missense_variant	Exon 25 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.4651G>T	p.Val1551Leu	missense_variant	Exon 25 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.4612G>T	p.Val1538Leu	missense_variant	Exon 25 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.4651G>T	p.Val1551Leu	missense_variant	Exon 25 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.4651G>T	p.Val1551Leu	missense_variant	Exon 25 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.4651G>T	p.Val1551Leu	missense_variant	Exon 25 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.4651G>T	p.Val1551Leu	missense_variant	Exon 25 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.4651G>T	p.Val1551Leu	missense_variant	Exon 25 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.4651G>T		non_coding_transcript_exon_variant	Exon 25 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.*621G>T		non_coding_transcript_exon_variant	Exon 25 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.4589G>T		non_coding_transcript_exon_variant	Exon 25 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2502G>T		non_coding_transcript_exon_variant	Exon 25 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*4036G>T		non_coding_transcript_exon_variant	Exon 24 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.4651G>T		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.4651G>T		non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.4651G>T		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.4651G>T		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.4651G>T		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.4651G>T		non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.4651G>T		non_coding_transcript_exon_variant	Exon 25 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.4651G>T		non_coding_transcript_exon_variant	Exon 25 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.4651G>T		non_coding_transcript_exon_variant	Exon 25 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3	n.*621G>T		3_prime_UTR_variant	Exon 25 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000640028.1	n.*2502G>T		3_prime_UTR_variant	Exon 25 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*4036G>T		3_prime_UTR_variant	Exon 24 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 02, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D;.
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		9.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D;.;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.027	D;.;D;D
Sift4G	Uncertain	0.0030	D;.;D;D
Polyphen		0.22	B;.;P;P
Vest4		0.78
MutPred		0.71		Loss of catalytic residue at V1551 (P = 0.0299);.;Loss of catalytic residue at V1551 (P = 0.0299);Loss of catalytic residue at V1551 (P = 0.0299);
MVP		0.92
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.69
gMVP		0.69
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs369045626; hg19: chr16-1262030;