16-1213792-G-T

Variant names:

• chr16-1213792-G-T
• rs370079169
• NM_021098.3:c.4790G>T

Variant summary

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

The NM_021098.3(CACNA1H):​c.4790G>T​(p.Arg1597Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000354 in 1,411,470 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1597W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• 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 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.4790G>T	p.Arg1597Leu	missense_variant	Exon 27 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4790G>T	p.Arg1597Leu	missense_variant	Exon 27 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.4805G>T	p.Arg1602Leu	missense_variant	Exon 26 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.4808G>T	p.Arg1603Leu	missense_variant	Exon 26 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.4772G>T	p.Arg1591Leu	missense_variant	Exon 26 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.4805G>T	p.Arg1602Leu	missense_variant	Exon 27 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.4790G>T	p.Arg1597Leu	missense_variant	Exon 27 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.4751G>T	p.Arg1584Leu	missense_variant	Exon 27 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.4772G>T	p.Arg1591Leu	missense_variant	Exon 26 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.4733G>T	p.Arg1578Leu	missense_variant	Exon 26 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.4790G>T	p.Arg1597Leu	missense_variant	Exon 27 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.4772G>T	p.Arg1591Leu	missense_variant	Exon 26 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.4790G>T	p.Arg1597Leu	missense_variant	Exon 27 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.4790G>T	p.Arg1597Leu	missense_variant	Exon 27 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.4790G>T	p.Arg1597Leu	missense_variant	Exon 27 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.4790G>T		non_coding_transcript_exon_variant	Exon 27 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.*742G>T		non_coding_transcript_exon_variant	Exon 26 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.4728G>T		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2641G>T		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*4234G>T		non_coding_transcript_exon_variant	Exon 25 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.4772G>T		non_coding_transcript_exon_variant	Exon 26 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.4772G>T		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.4867G>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.4790G>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.4790G>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.4772G>T		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.4790G>T		non_coding_transcript_exon_variant	Exon 27 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.4790G>T		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.4849G>T		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3	n.*742G>T		3_prime_UTR_variant	Exon 26 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000640028.1	n.*2641G>T		3_prime_UTR_variant	Exon 27 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*4234G>T		3_prime_UTR_variant	Exon 25 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000354 AC: 5 AN: 1411470 Hom.: 0 Cov.: 31 AF XY: 0.00000573 AC XY: 4 AN XY: 698010

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32370

American (AMR) AF: 0.00 AC: 0 AN: 37114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25366

East Asian (EAS) AF: 0.00 AC: 0 AN: 37066

South Asian (SAS) AF: 0.00 AC: 0 AN: 80776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00000459 AC: 5 AN: 1088816

Other (OTH) AF: 0.00 AC: 0 AN: 58736

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00353856), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.87	D;D;T;.
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	0.0	.;.;.;.
PhyloP100		1.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.4	D;.;D;D
REVEL	Uncertain	0.58
Sift	Benign	0.35	T;.;T;T
Sift4G	Benign	0.23	T;.;T;T
Vest4		0.68
ClinPred		0.96	D
GERP RS		3.9
Varity_R		0.31
gMVP		0.72
Mutation Taster		=77/23	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: rs370079169; hg19: chr16-1263792;