16-1210967-C-G

Variant names:

• chr16-1210967-C-G
• NM_021098.3:c.4219C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021098.3(CACNA1H):​c.4219C>G​(p.Leu1407Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,443,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1407L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.00

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4219C>G	p.Leu1407Val	missense_variant	Exon 21 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4219C>G	p.Leu1407Val	missense_variant	Exon 21 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4219C>G	p.Leu1407Val	missense_variant	Exon 20 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4180C>G	p.Leu1394Val	missense_variant	Exon 21 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.442C>G	p.Leu148Val	missense_variant	Exon 4 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.442C>G	p.Leu148Val	missense_variant	Exon 4 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.442C>G	p.Leu148Val	missense_variant	Exon 4 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000637236.2	n.*189C>G		non_coding_transcript_exon_variant	Exon 5 of 6	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.4219C>G		non_coding_transcript_exon_variant	Exon 21 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2132C>G		non_coding_transcript_exon_variant	Exon 21 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000637236.2	n.*189C>G		3_prime_UTR_variant	Exon 5 of 6	5		ENSP00000492650.2
CACNA1H	ENST00000640028.1	n.*2132C>G		3_prime_UTR_variant	Exon 21 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443036 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 717558

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D;D;.
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;.;M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.9	D;.;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.024	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.71
MutPred		0.70		Gain of MoRF binding (P = 0.1113);.;Gain of MoRF binding (P = 0.1113);Gain of MoRF binding (P = 0.1113);
MVP		0.92
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.82
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-1260967;