16-1211508-G-T

Variant names:

• chr16-1211508-G-T
• rs755817927
• NM_021098.3:c.4378G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP3

The NM_021098.3(CACNA1H):​c.4378G>T​(p.Glu1460*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1H NM_021098.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.85
• Publications: 3 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4378G>T	p.Glu1460*	stop_gained	Exon 23 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4378G>T	p.Glu1460*	stop_gained	Exon 23 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.4378G>T	p.Glu1460*	stop_gained	Exon 23 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.4414G>T	p.Glu1472*	stop_gained	Exon 23 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.4378G>T	p.Glu1460*	stop_gained	Exon 23 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.4378G>T	p.Glu1460*	stop_gained	Exon 23 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.4378G>T	p.Glu1460*	stop_gained	Exon 23 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.4339G>T	p.Glu1447*	stop_gained	Exon 23 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.4378G>T	p.Glu1460*	stop_gained	Exon 23 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.4339G>T	p.Glu1447*	stop_gained	Exon 23 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.4378G>T	p.Glu1460*	stop_gained	Exon 23 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.4378G>T	p.Glu1460*	stop_gained	Exon 23 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.4378G>T	p.Glu1460*	stop_gained	Exon 23 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.4378G>T	p.Glu1460*	stop_gained	Exon 23 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.4378G>T	p.Glu1460*	stop_gained	Exon 23 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.4378G>T		non_coding_transcript_exon_variant	Exon 23 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.*348G>T		non_coding_transcript_exon_variant	Exon 23 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.4378G>T		non_coding_transcript_exon_variant	Exon 23 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2291G>T		non_coding_transcript_exon_variant	Exon 23 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*3825G>T		non_coding_transcript_exon_variant	Exon 22 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.4378G>T		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.4378G>T		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.4378G>T		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.4378G>T		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.4378G>T		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.4378G>T		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.4378G>T		non_coding_transcript_exon_variant	Exon 23 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.4378G>T		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.4378G>T		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3	n.*348G>T		3_prime_UTR_variant	Exon 23 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000640028.1	n.*2291G>T		3_prime_UTR_variant	Exon 23 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*3825G>T		3_prime_UTR_variant	Exon 22 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.000136 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	58
DANN	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		3.8
Vest4		0.83
GERP RS		4.2
Mutation Taster		=6/194	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.62		Position offset: 3
DS_AL_spliceai		0.20		Position offset: -27

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs755817927; hg19: chr16-1261508;