16-1218275-C-T

Variant names:

• chr16-1218275-C-T
• rs58819745
• NM_021098.3:c.5511C>T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_021098.3(CACNA1H):​c.5511C>T​(p.Pro1837Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,552,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.830

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 16-1218275-C-T is Benign according to our data. Variant chr16-1218275-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.83 with no splicing effect.
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5511C>T	p.Pro1837Pro	synonymous_variant	Exon 33 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5511C>T	p.Pro1837Pro	synonymous_variant	Exon 33 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.5493C>T	p.Pro1831Pro	synonymous_variant	Exon 31 of 33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.5472C>T	p.Pro1824Pro	synonymous_variant	Exon 33 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1749C>T	p.Pro583Pro	synonymous_variant	Exon 15 of 17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1734C>T	p.Pro578Pro	synonymous_variant	Exon 16 of 18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1716C>T	p.Pro572Pro	synonymous_variant	Exon 15 of 17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*592C>T		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3362C>T		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*592C>T		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3362C>T		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152230 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000501 AC: 8 AN: 159816 Hom.: 0 AF XY: 0.0000355 AC XY: 3 AN XY: 84562

Gnomad AFR exome AF: 0.000121

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000453

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000604

Gnomad NFE exome AF: 0.0000158

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 21 AN: 1399926 Hom.: 0 Cov.: 32 AF XY: 0.0000101 AC XY: 7 AN XY: 690650

Gnomad4 AFR exome AF: 0.000126

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.000112

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.0000207

Gnomad4 NFE exome AF: 0.00000741

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152230 Hom.: 0 Cov.: 34 AF XY: 0.0000672 AC XY: 5 AN XY: 74374

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Apr 20, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.8
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs58819745; hg19: chr16-1268275;