chr16-1211508-G-A

Variant names:

• chr16-1211508-G-A
• rs755817927
• NM_021098.3:c.4378G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_021098.3(CACNA1H):​c.4378G>A​(p.Glu1460Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000146 in 1,612,340 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 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.85
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14111176).
• BP6: Variant 16-1211508-G-A is Benign according to our data. Variant chr16-1211508-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 460115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1	c.4414G>A	p.Glu1472Lys	missense_variant	Exon 23 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1	c.4339G>A	p.Glu1447Lys	missense_variant	Exon 23 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1	c.4339G>A	p.Glu1447Lys	missense_variant	Exon 23 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3	n.*348G>A		non_coding_transcript_exon_variant	Exon 23 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2291G>A		non_coding_transcript_exon_variant	Exon 23 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*3825G>A		non_coding_transcript_exon_variant	Exon 22 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3	n.*348G>A		3_prime_UTR_variant	Exon 23 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000640028.1	n.*2291G>A		3_prime_UTR_variant	Exon 23 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1	n.*3825G>A		3_prime_UTR_variant	Exon 22 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000250 AC: 62 AN: 247634 AF XY: 0.000230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000140 AC: 205 AN: 1460160 Hom.: 0 Cov.: 35 AF XY: 0.000138 AC XY: 100 AN XY: 726374

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.000112 AC: 5 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00161 AC: 84 AN: 52106

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000819 AC: 91 AN: 1111698

Other (OTH) AF: 0.000298 AC: 18 AN: 60340

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74340

African (AFR) AF: 0.0000724 AC: 3 AN: 41442

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000146 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000199 AC: 24

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1H: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;.;.
Eigen	Benign	0.092
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;.
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.4	L;.;L;L
PhyloP100		3.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N;.;N;N
REVEL	Uncertain	0.60
Sift	Benign	0.24	T;.;T;T
Sift4G	Benign	0.59	T;.;T;T
Polyphen		0.91	P;.;B;B
Vest4		0.61
MVP		0.82
ClinPred		0.11	T
GERP RS		4.2
Varity_R		0.28
gMVP		0.74
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs755817927; hg19: chr16-1261508;