rs775405041

Variant names:

• chr16-1209326-C-G
• rs775405041
• NM_021098.3:c.3658C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_021098.3(CACNA1H):​c.3658C>G​(p.Gln1220Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,597,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1220R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.13
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3066622).
• BP6: Variant 16-1209326-C-G is Benign according to our data. Variant chr16-1209326-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 566607.
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.3658C>G	p.Gln1220Glu	missense_variant	Exon 17 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.3658C>G	p.Gln1220Glu	missense_variant	Exon 17 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.3658C>G	p.Gln1220Glu	missense_variant	Exon 17 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.3658C>G	p.Gln1220Glu	missense_variant	Exon 17 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.3658C>G	p.Gln1220Glu	missense_variant	Exon 17 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.3658C>G	p.Gln1220Glu	missense_variant	Exon 17 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.3658C>G	p.Gln1220Glu	missense_variant	Exon 17 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.3619C>G	p.Gln1207Glu	missense_variant	Exon 17 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.3658C>G	p.Gln1220Glu	missense_variant	Exon 17 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.3619C>G	p.Gln1207Glu	missense_variant	Exon 17 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.3658C>G	p.Gln1220Glu	missense_variant	Exon 17 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.3658C>G	p.Gln1220Glu	missense_variant	Exon 17 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.3658C>G	p.Gln1220Glu	missense_variant	Exon 17 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.3658C>G	p.Gln1220Glu	missense_variant	Exon 17 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.3658C>G	p.Gln1220Glu	missense_variant	Exon 17 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.3658C>G		non_coding_transcript_exon_variant	Exon 17 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.3658C>G		non_coding_transcript_exon_variant	Exon 17 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.3658C>G		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1571C>G		non_coding_transcript_exon_variant	Exon 17 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*3105C>G		non_coding_transcript_exon_variant	Exon 16 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.3658C>G		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.3658C>G		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.3658C>G		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.3658C>G		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.3658C>G		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.3658C>G		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.3658C>G		non_coding_transcript_exon_variant	Exon 17 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.3658C>G		non_coding_transcript_exon_variant	Exon 17 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.3658C>G		non_coding_transcript_exon_variant	Exon 17 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1	n.*1571C>G		3_prime_UTR_variant	Exon 17 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*3105C>G		3_prime_UTR_variant	Exon 16 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000875 AC: 2 AN: 228464 AF XY: 0.00

Gnomad AFR exome AF: 0.0000723

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000484 AC: 7 AN: 1445596 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 719582

African (AFR) AF: 0.000149 AC: 5 AN: 33450

American (AMR) AF: 0.0000224 AC: 1 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111300

Other (OTH) AF: 0.0000166 AC: 1 AN: 60220

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74372

African (AFR) AF: 0.000265 AC: 11 AN: 41470

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.00000850 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1

Jan 06, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Benign	0.75
DEOGEN2	Benign	0.10	T;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.76	T;T;T;.
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.7	M;.;M;M
PhyloP100		3.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.68	N;.;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.084	T;.;T;T
Sift4G	Benign	0.32	T;.;T;T
Polyphen		0.87	P;.;B;B
Vest4		0.36
MutPred		0.21		Loss of catalytic residue at Q1220 (P = 0.1879);.;Loss of catalytic residue at Q1220 (P = 0.1879);Loss of catalytic residue at Q1220 (P = 0.1879);
MVP		0.85
ClinPred		0.11	T
GERP RS		4.1
Varity_R		0.16
gMVP		0.44
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: rs775405041; hg19: chr16-1259326;