chr16-1220372-C-A

Variant names:

• chr16-1220372-C-A
• rs748980218
• NM_021098.3:c.6440C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021098.3(CACNA1H):​c.6440C>A​(p.Pro2147Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,370,052 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.44

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6440C>A	p.Pro2147Gln	missense_variant	Exon 35 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6440C>A	p.Pro2147Gln	missense_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.6422C>A	p.Pro2141Gln	missense_variant	Exon 33 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.6401C>A	p.Pro2134Gln	missense_variant	Exon 35 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.2678C>A	p.Pro893Gln	missense_variant	Exon 17 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.2630C>A	p.Pro877Gln	missense_variant	Exon 18 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.2612C>A	p.Pro871Gln	missense_variant	Exon 17 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*1488C>A		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4258C>A		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*1488C>A		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4258C>A		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1370052 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 675736

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000177

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CACNA1H c.6440C>A (p.Pro2147Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.6440C>A in individuals affected with Idiopathic Generalized Epilepsy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2069974). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Dec 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 2147 of the CACNA1H protein (p.Pro2147Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1H protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T;T;T;.
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.1	D;.;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0020	D;.;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.22
MutPred		0.30		Gain of MoRF binding (P = 0.0517);.;.;.;
MVP		0.92
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.33
gMVP		0.32

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: rs748980218; hg19: chr16-1270372;