16-1204068-C-A

Variant names:

• chr16-1204068-C-A
• rs554718345
• NM_021098.3:c.2061C>A

Variant summary

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

The NM_021098.3(CACNA1H):​c.2061C>A​(p.Ser687Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S687S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.831
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.2061C>A	p.Ser687Arg	missense_variant	Exon 10 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.2061C>A	p.Ser687Arg	missense_variant	Exon 10 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.2061C>A	p.Ser687Arg	missense_variant	Exon 10 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.2061C>A	p.Ser687Arg	missense_variant	Exon 10 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.2061C>A	p.Ser687Arg	missense_variant	Exon 10 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.2061C>A	p.Ser687Arg	missense_variant	Exon 10 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.2061C>A	p.Ser687Arg	missense_variant	Exon 10 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.2022C>A	p.Ser674Arg	missense_variant	Exon 10 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.2061C>A	p.Ser687Arg	missense_variant	Exon 10 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.2022C>A	p.Ser674Arg	missense_variant	Exon 10 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.2061C>A	p.Ser687Arg	missense_variant	Exon 10 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.2061C>A	p.Ser687Arg	missense_variant	Exon 10 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.2061C>A	p.Ser687Arg	missense_variant	Exon 10 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.2061C>A	p.Ser687Arg	missense_variant	Exon 10 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.2061C>A	p.Ser687Arg	missense_variant	Exon 10 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.2061C>A		non_coding_transcript_exon_variant	Exon 10 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.2061C>A		non_coding_transcript_exon_variant	Exon 10 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.2061C>A		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.1444C>A		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*1508C>A		non_coding_transcript_exon_variant	Exon 9 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.2061C>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.2061C>A		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.2061C>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.2061C>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.2061C>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.2061C>A		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.2061C>A		non_coding_transcript_exon_variant	Exon 10 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.2061C>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.2061C>A		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1	n.*1508C>A		3_prime_UTR_variant	Exon 9 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448588 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719476

African (AFR) AF: 0.00 AC: 0 AN: 33218

American (AMR) AF: 0.00 AC: 0 AN: 43378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25864

East Asian (EAS) AF: 0.00 AC: 0 AN: 39124

South Asian (SAS) AF: 0.00 AC: 0 AN: 84096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106666

Other (OTH) AF: 0.00 AC: 0 AN: 59868

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;.
Eigen	Benign	0.055
Eigen_PC	Benign	-0.049
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;T;T;.
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.3	M;.;M;M
PhyloP100		0.83
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	N;.;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.017	D;.;D;D
Sift4G	Benign	0.11	T;.;T;T
Polyphen		1.0	D;.;D;D
Vest4		0.46
MutPred		0.20		Loss of glycosylation at S687 (P = 0.0094);.;Loss of glycosylation at S687 (P = 0.0094);Loss of glycosylation at S687 (P = 0.0094);
MVP		0.93
ClinPred		0.88	D
GERP RS		0.66
Varity_R		0.12
gMVP		0.42
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs554718345; hg19: chr16-1254068;