rs59286323

Positions:

• chr16-1213819-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.4817C>T​(p.Thr1606Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 1,584,426 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (54 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.994

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014217705).
• BP6: Variant 16-1213819-C-T is Benign according to our data. Variant chr16-1213819-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 96013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1213819-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00479 (729/152210) while in subpopulation NFE AF= 0.00806 (548/67982). AF 95% confidence interval is 0.0075. There are 2 homozygotes in gnomad4. There are 344 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 729 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4817C>T	p.Thr1606Met	missense_variant	27/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4817C>T	p.Thr1606Met	missense_variant	27/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4799C>T	p.Thr1600Met	missense_variant	25/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4778C>T	p.Thr1593Met	missense_variant	27/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1055C>T	p.Thr352Met	missense_variant	9/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1040C>T	p.Thr347Met	missense_variant	10/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1022C>T	p.Thr341Met	missense_variant	9/17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.4755C>T		non_coding_transcript_exon_variant	27/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2668C>T		non_coding_transcript_exon_variant	27/35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*2668C>T		3_prime_UTR_variant	27/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 730 AN: 152092 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00806

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00501 AC: 1010 AN: 201458 Hom.: 4 AF XY: 0.00519 AC XY: 566 AN XY: 109128

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.000762

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00426

Gnomad FIN exome AF: 0.00435

Gnomad NFE exome AF: 0.00797

Gnomad OTH exome AF: 0.00667

GnomAD4 exome AF: 0.00720 AC: 10312 AN: 1432216 Hom.: 54 Cov.: 31 AF XY: 0.00715 AC XY: 5073 AN XY: 709850

Gnomad4 AFR exome AF: 0.00112

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00121

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00389

Gnomad4 FIN exome AF: 0.00474

Gnomad4 NFE exome AF: 0.00842

Gnomad4 OTH exome AF: 0.00565

GnomAD4 genome AF: 0.00479 AC: 729 AN: 152210 Hom.: 2 Cov.: 32 AF XY: 0.00462 AC XY: 344 AN XY: 74414

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00490

Gnomad4 NFE AF: 0.00806

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00674 Hom.: 3

Bravo AF: 0.00448

ESP6500AA AF: 0.00195 AC: 8

ESP6500EA AF: 0.00798 AC: 67

ExAC AF: 0.00498 AC: 597

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CACNA1H: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 14, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2013	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 10, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T;.;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.88	D;D;D;.
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Uncertain	0.47	D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.0	N;.;N;N
REVEL	Uncertain	0.50
Sift	Benign	0.22	T;.;T;T
Sift4G	Benign	0.24	T;.;T;T
Polyphen		0.28	B;.;P;P
Vest4		0.57
MVP		0.89
ClinPred		0.013	T
GERP RS		3.9
Varity_R		0.086
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs59286323; hg19: chr16-1263819;