chr16-1153791-G-C

Variant names:

• chr16-1153791-G-C
• rs1337167126
• NM_021098.3:c.54G>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP7 BS2

The NM_021098.3(CACNA1H):​c.54G>C​(p.Pro18Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000464 in 1,078,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P18P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0440
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hyperaldosteronism, familial, type IV

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, childhood absence, susceptibility to, 6

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP7: Synonymous conserved (PhyloP=0.044 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.54G>C	p.Pro18Pro	synonymous	Exon 2 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.54G>C	p.Pro18Pro	synonymous	Exon 2 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.54G>C	p.Pro18Pro	synonymous	Exon 2 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.54G>C	p.Pro18Pro	synonymous	Exon 2 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.54G>C	p.Pro18Pro	synonymous	Exon 2 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000464 AC: 5 AN: 1078738 Hom.: 0 Cov.: 32 AF XY: 0.00000391 AC XY: 2 AN XY: 511980

African (AFR) AF: 0.00 AC: 0 AN: 22064

American (AMR) AF: 0.00 AC: 0 AN: 7686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13452

East Asian (EAS) AF: 0.00 AC: 0 AN: 24444

South Asian (SAS) AF: 0.0000802 AC: 2 AN: 24940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2832

European-Non Finnish (NFE) AF: 0.00000327 AC: 3 AN: 918740

Other (OTH) AF: 0.00 AC: 0 AN: 42712

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.67
PhyloP100		0.044
PromoterAI		0.081	Neutral

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

Other links and lift over

dbSNP: rs1337167126; hg19: chr16-1203791;