NM_021098.3:c.4645A>G

Variant names:

• chr16-1212024-A-G
• rs786205050
• NM_021098.3:c.4645A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_021098.3(CACNA1H):​c.4645A>G​(p.Met1549Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1549I) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.18

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 16-1212024-A-G is Pathogenic according to our data. Variant chr16-1212024-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 189779.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4645A>G	p.Met1549Val	missense_variant	Exon 25 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4645A>G	p.Met1549Val	missense_variant	Exon 25 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4645A>G	p.Met1549Val	missense_variant	Exon 24 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4606A>G	p.Met1536Val	missense_variant	Exon 25 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.868A>G	p.Met290Val	missense_variant	Exon 8 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.868A>G	p.Met290Val	missense_variant	Exon 8 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.868A>G	p.Met290Val	missense_variant	Exon 8 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.4583A>G		non_coding_transcript_exon_variant	Exon 25 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2496A>G		non_coding_transcript_exon_variant	Exon 25 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*2496A>G		3_prime_UTR_variant	Exon 25 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74310

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperaldosteronism, familial, type IV Pathogenic:1

Apr 24, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 15, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging gain of function effect as this variant results in the calcium channels remaining open longer (Scholl et al., 2015; Gurtler et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35757409, 27729216, 35813615, 35139664, 32638069, 29229745, 33142317, 29642543, 27242667, 33900205, 33704440, 31217264, 29594118, 30964584, 29735637, 26445452, 27315758, 28974569, 32227660, 27485459, 31983310, 27445978, 28933792, 31695023, 27527004, 27258646, 33879608, 32785697, 25907736) -

Primary aldosteronism Pathogenic:1

Mar 20, 2015

Richard Lifton Laboratory, Yale University School of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;.;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D;D;D;.
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	D;.;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.011	D;.;D;D
Sift4G	Uncertain	0.0020	D;.;D;D
Polyphen		0.36	B;.;B;B
Vest4		0.80
MutPred		0.74		Gain of sheet (P = 0.0073);.;Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);
MVP		0.97
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.62
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs786205050; hg19: chr16-1262024;