rs376628149

Positions:

• chr16-1219071-G-A
• chr16-1219071-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_021098.3(CACNA1H):​c.5989G>A​(p.Ala1997Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,549,756 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.40

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012807757).
• BP6: Variant 16-1219071-G-A is Benign according to our data. Variant chr16-1219071-G-A is described in ClinVar as [Benign]. Clinvar id is 529696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-1219071-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00042 (64/152308) while in subpopulation EAS AF= 0.00617 (32/5188). AF 95% confidence interval is 0.00449. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5989G>A	p.Ala1997Thr	missense_variant	34/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5989G>A	p.Ala1997Thr	missense_variant	34/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.5971G>A	p.Ala1991Thr	missense_variant	32/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.5950G>A	p.Ala1984Thr	missense_variant	34/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.2227G>A	p.Ala743Thr	missense_variant	16/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.2179G>A	p.Ala727Thr	missense_variant	17/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.2161G>A	p.Ala721Thr	missense_variant	16/17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*1037G>A		non_coding_transcript_exon_variant	34/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3807G>A		non_coding_transcript_exon_variant	34/35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*1037G>A		3_prime_UTR_variant	34/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3807G>A		3_prime_UTR_variant	34/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152190 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00615

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000659 AC: 100 AN: 151836 Hom.: 0 AF XY: 0.000679 AC XY: 55 AN XY: 81008

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00620

Gnomad SAS exome AF: 0.00106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.000210 AC: 294 AN: 1397448 Hom.: 1 Cov.: 34 AF XY: 0.000242 AC XY: 167 AN XY: 689272

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00277

Gnomad4 SAS exome AF: 0.00120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000287

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152308 Hom.: 0 Cov.: 34 AF XY: 0.000524 AC XY: 39 AN XY: 74474

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00617

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.000329

ExAC AF: 0.000300 AC: 20

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	0.17
DANN	Benign	0.89
DEOGEN2	Benign	0.12	T;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.38	T;T;T;.
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Uncertain	0.00090	D
MutationAssessor	Benign	0.77	N;.;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.53	N;.;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.44	T;.;T;T
Sift4G	Benign	0.57	T;.;T;T
Polyphen		0.0010	B;.;B;B
Vest4		0.035
MVP		0.80
ClinPred		0.0059	T
GERP RS		-3.9
Varity_R		0.056
gMVP		0.21

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: rs376628149; hg19: chr16-1269071;