rs267606697

Variant names:

• chr16-1204325-G-A
• rs267606697
• NM_021098.3:c.2318G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1204325-G-A
• chr16-1204325-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.2318G>A​(p.Gly773Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000583 in 1,595,922 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.278
• Publications: 14 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.109641224).
• BP6: Variant 16-1204325-G-A is Benign according to our data. Variant chr16-1204325-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 242815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000722 (11/152384) while in subpopulation EAS AF = 0.00193 (10/5188). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.2318G>A	p.Gly773Asp	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.2318G>A	p.Gly773Asp	missense_variant	Exon 10 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.2318G>A	p.Gly773Asp	missense_variant	Exon 10 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.2318G>A	p.Gly773Asp	missense_variant	Exon 10 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.2318G>A	p.Gly773Asp	missense_variant	Exon 10 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.2318G>A	p.Gly773Asp	missense_variant	Exon 10 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.2318G>A	p.Gly773Asp	missense_variant	Exon 10 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.2279G>A	p.Gly760Asp	missense_variant	Exon 10 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.2318G>A	p.Gly773Asp	missense_variant	Exon 10 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.2279G>A	p.Gly760Asp	missense_variant	Exon 10 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.2318G>A	p.Gly773Asp	missense_variant	Exon 10 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.2318G>A	p.Gly773Asp	missense_variant	Exon 10 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.2318G>A	p.Gly773Asp	missense_variant	Exon 10 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.2318G>A	p.Gly773Asp	missense_variant	Exon 10 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.2318G>A	p.Gly773Asp	missense_variant	Exon 10 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.2318G>A		non_coding_transcript_exon_variant	Exon 10 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.2318G>A		non_coding_transcript_exon_variant	Exon 10 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.2318G>A		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*231G>A		non_coding_transcript_exon_variant	Exon 10 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*1765G>A		non_coding_transcript_exon_variant	Exon 9 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.2318G>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.2318G>A		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.2318G>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.2318G>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.2318G>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.2318G>A		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.2318G>A		non_coding_transcript_exon_variant	Exon 10 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.2318G>A		non_coding_transcript_exon_variant	Exon 10 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.2318G>A		non_coding_transcript_exon_variant	Exon 10 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1	n.*231G>A		3_prime_UTR_variant	Exon 10 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*1765G>A		3_prime_UTR_variant	Exon 9 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes AF: 0.0000722 AC: 11 AN: 152266 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000236 AC: 55 AN: 233190 AF XY: 0.000290

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00301

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000955

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.0000568 AC: 82 AN: 1443538 Hom.: 0 Cov.: 32 AF XY: 0.0000657 AC XY: 47 AN XY: 715652

African (AFR) AF: 0.00 AC: 0 AN: 33034

American (AMR) AF: 0.00 AC: 0 AN: 43286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25234

East Asian (EAS) AF: 0.00191 AC: 75 AN: 39302

South Asian (SAS) AF: 0.00 AC: 0 AN: 84372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51370

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5680

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1101736

Other (OTH) AF: 0.0000504 AC: 3 AN: 59524

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152384 Hom.: 0 Cov.: 33 AF XY: 0.0000939 AC XY: 7 AN XY: 74522

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.000267 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Apr 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Benign	0.67
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.61	T;T;T;.
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Uncertain	0.094	D
MutationAssessor	Uncertain	2.2	M;.;M;M
PhyloP100		0.28
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.75	N;.;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.30	T;.;T;T
Sift4G	Benign	0.43	T;.;T;T
Polyphen		0.48	P;.;P;P
Vest4		0.58
MutPred		0.75		Loss of catalytic residue at P769 (P = 0.0722);.;Loss of catalytic residue at P769 (P = 0.0722);Loss of catalytic residue at P769 (P = 0.0722);
MVP		1.0
ClinPred		0.073	T
GERP RS		3.2
Varity_R		0.082
gMVP		0.37
Mutation Taster		=89/11	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: rs267606697; hg19: chr16-1254325;