rs749735503

Positions:

• chr16-1153917-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_021098.3(CACNA1H):​c.180G>C​(p.Ala60=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00066 in 1,455,098 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00068 (2 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0570

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 16-1153917-G-C is Benign according to our data. Variant chr16-1153917-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 529649.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.057 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000455 (69/151490) while in subpopulation NFE AF= 0.00087 (59/67784). AF 95% confidence interval is 0.000692. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.180G>C	p.Ala60=	synonymous_variant	2/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.180G>C	p.Ala60=	synonymous_variant	2/35	1	NM_021098.3	ENSP00000334198	P4

Frequencies

GnomAD3 genomes AF: 0.000455 AC: 69 AN: 151490 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000961

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000870

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.000311 AC: 25 AN: 80370 Hom.: 0 AF XY: 0.000283 AC XY: 13 AN XY: 45982

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000628

Gnomad ASJ exome AF: 0.00121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000172

Gnomad NFE exome AF: 0.000523

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000683 AC: 891 AN: 1303608 Hom.: 2 Cov.: 32 AF XY: 0.000693 AC XY: 445 AN XY: 641838

Gnomad4 AFR exome AF: 0.0000378

Gnomad4 AMR exome AF: 0.000226

Gnomad4 ASJ exome AF: 0.000919

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000139

Gnomad4 FIN exome AF: 0.000148

Gnomad4 NFE exome AF: 0.000795

Gnomad4 OTH exome AF: 0.000598

GnomAD4 genome AF: 0.000455 AC: 69 AN: 151490 Hom.: 0 Cov.: 30 AF XY: 0.000243 AC XY: 18 AN XY: 73958

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000961

Gnomad4 NFE AF: 0.000870

Gnomad4 OTH AF: 0.000482

Alfa AF: 0.000788 Hom.: 0

Bravo AF: 0.000450

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2016

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.5
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs749735503; hg19: chr16-1203917;