rs1555512240

Variant names:

• chr16-1202365-G-A
• rs1555512240
• NM_021098.3:c.1915G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1202365-G-A
• chr16-1202365-G-T

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.1915G>A​(p.Gly639Arg) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0470
• 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=0.16202587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.1915G>A	p.Gly639Arg	missense_variant	Exon 9 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1915G>A	p.Gly639Arg	missense_variant	Exon 9 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.1915G>A	p.Gly639Arg	missense_variant	Exon 9 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.1915G>A	p.Gly639Arg	missense_variant	Exon 9 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.1915G>A	p.Gly639Arg	missense_variant	Exon 9 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.1915G>A	p.Gly639Arg	missense_variant	Exon 9 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.1915G>A	p.Gly639Arg	missense_variant	Exon 9 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.1876G>A	p.Gly626Arg	missense_variant	Exon 9 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.1915G>A	p.Gly639Arg	missense_variant	Exon 9 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.1876G>A	p.Gly626Arg	missense_variant	Exon 9 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.1915G>A	p.Gly639Arg	missense_variant	Exon 9 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.1915G>A	p.Gly639Arg	missense_variant	Exon 9 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.1915G>A	p.Gly639Arg	missense_variant	Exon 9 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.1915G>A	p.Gly639Arg	missense_variant	Exon 9 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.1915G>A	p.Gly639Arg	missense_variant	Exon 9 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.1915G>A		non_coding_transcript_exon_variant	Exon 9 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.1915G>A		non_coding_transcript_exon_variant	Exon 9 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.1915G>A		non_coding_transcript_exon_variant	Exon 9 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000711442.1	n.*1362G>A		non_coding_transcript_exon_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.1915G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.1915G>A		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.1915G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.1915G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.1915G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.1915G>A		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.1915G>A		non_coding_transcript_exon_variant	Exon 9 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.1915G>A		non_coding_transcript_exon_variant	Exon 9 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.1915G>A		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1	n.*1362G>A		3_prime_UTR_variant	Exon 8 of 34			ENSP00000518758.1
CACNA1H	ENST00000640028.1	n.1385+530G>A		intron_variant	Intron 9 of 34	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1408754 Hom.: 0 Cov.: 57 AF XY: 0.00 AC XY: 0 AN XY: 696206

African (AFR) AF: 0.00 AC: 0 AN: 32118

American (AMR) AF: 0.00 AC: 0 AN: 37134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25200

East Asian (EAS) AF: 0.00 AC: 0 AN: 36380

South Asian (SAS) AF: 0.00 AC: 0 AN: 79696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086852

Other (OTH) AF: 0.00 AC: 0 AN: 58444

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6 Uncertain:1

Sep 08, 2017

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	7.0
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.65	T;T;T;.
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.4	L;.;L;L
PhyloP100		0.047
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.0	N;.;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.54	T;.;T;T
Sift4G	Benign	0.52	T;.;T;T
Polyphen		0.58	P;.;P;P
Vest4		0.11
MutPred		0.30		Gain of MoRF binding (P = 0.0169);.;Gain of MoRF binding (P = 0.0169);Gain of MoRF binding (P = 0.0169);
MVP		0.80
ClinPred		0.43	T
GERP RS		0.93
Varity_R		0.11
gMVP		0.45
Mutation Taster		=92/8	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: rs1555512240; hg19: chr16-1252365;