16-1219055-C-A

Variant names:

• chr16-1219055-C-A
• rs753397534
• NM_021098.3:c.5973C>A

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.5973C>A​(p.Ser1991Arg) 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. 14/22 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. S1991S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03
• 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=0.12485269).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5973C>A	p.Ser1991Arg	missense_variant	Exon 34 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5973C>A	p.Ser1991Arg	missense_variant	Exon 34 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.5988C>A	p.Ser1996Arg	missense_variant	Exon 33 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.5958C>A	p.Ser1986Arg	missense_variant	Exon 33 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.5955C>A	p.Ser1985Arg	missense_variant	Exon 33 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.5955C>A	p.Ser1985Arg	missense_variant	Exon 34 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.5940C>A	p.Ser1980Arg	missense_variant	Exon 34 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.5934C>A	p.Ser1978Arg	missense_variant	Exon 34 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.5922C>A	p.Ser1974Arg	missense_variant	Exon 33 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.5916C>A	p.Ser1972Arg	missense_variant	Exon 33 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.5973C>A	p.Ser1991Arg	missense_variant	Exon 34 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.5922C>A	p.Ser1974Arg	missense_variant	Exon 33 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.5895C>A	p.Ser1965Arg	missense_variant	Exon 34 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.5973C>A	p.Ser1991Arg	missense_variant	Exon 34 of 35			ENSP00000518772.1
CACNA1H	ENST00000621827.2	n.5973C>A		non_coding_transcript_exon_variant	Exon 34 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.*1892C>A		non_coding_transcript_exon_variant	Exon 33 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*1021C>A		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3791C>A		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*5417C>A		non_coding_transcript_exon_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*914C>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*832C>A		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*1552C>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*640C>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*607C>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.5922C>A		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.5973C>A		non_coding_transcript_exon_variant	Exon 34 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.5940C>A		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.*1089C>A		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3	n.*1892C>A		3_prime_UTR_variant	Exon 33 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.*1021C>A		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3791C>A		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*5417C>A		3_prime_UTR_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.*914C>A		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.*832C>A		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.*1552C>A		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.*640C>A		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.*607C>A		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518765.1
CACNA1H	ENST00000711488.1	n.*1089C>A		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000711456.1	c.5887+404C>A		intron_variant	Intron 33 of 33			ENSP00000518769.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1H protein function. ClinVar contains an entry for this variant (Variation ID: 572843). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1991 of the CACNA1H protein (p.Ser1991Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	7.7
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;.;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.67	T;T;T;.
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.0	L;.;.;.
PhyloP100		1.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N;.;N;N
REVEL	Benign	0.23
Sift	Benign	0.27	T;.;T;T
Sift4G	Benign	0.52	T;.;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.072
MutPred		0.23		Loss of phosphorylation at S1991 (P = 0.0077);.;.;.;
MVP		0.78
ClinPred		0.64	D
GERP RS		2.9
Varity_R		0.072
gMVP		0.27
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs753397534; hg19: chr16-1269055;