16-1215066-G-T

Variant names:

• chr16-1215066-G-T
• NM_021098.3:c.5024G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021098.3(CACNA1H):​c.5024G>T​(p.Arg1675Leu) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5024G>T	p.Arg1675Leu	missense_variant	Exon 28 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5024G>T	p.Arg1675Leu	missense_variant	Exon 28 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.5006G>T	p.Arg1669Leu	missense_variant	Exon 26 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4985G>T	p.Arg1662Leu	missense_variant	Exon 28 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1262G>T	p.Arg421Leu	missense_variant	Exon 10 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1247G>T	p.Arg416Leu	missense_variant	Exon 11 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1229G>T	p.Arg410Leu	missense_variant	Exon 10 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*105G>T		non_coding_transcript_exon_variant	Exon 28 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2875G>T		non_coding_transcript_exon_variant	Exon 28 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*105G>T		3_prime_UTR_variant	Exon 28 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2875G>T		3_prime_UTR_variant	Exon 28 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 13, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency 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	0.89
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;.
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.9	D;.;D;D
REVEL	Pathogenic	0.86
Sift	Benign	0.11	T;.;T;T
Sift4G	Benign	0.16	T;.;T;T
Polyphen		0.98	D;.;D;D
Vest4		0.86
MutPred		0.64		Loss of MoRF binding (P = 0.0269);.;.;.;
MVP		0.98
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.70
gMVP		0.81

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-1265066;