16-1218485-C-T

Position:

• chr16-1218485-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021098.3(CACNA1H):​c.5721C>T​(p.Gly1907Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,551,744 control chromosomes in the GnomAD database, including 14,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (919 hom., cov: 34)
  • Exomes 𝑓: 0.13 (13304 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.129

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 16-1218485-C-T is Benign according to our data. Variant chr16-1218485-C-T is described in ClinVar as [Benign]. Clinvar id is 585652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1218485-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.129 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.5721C>T	p.Gly1907Gly	synonymous_variant	33/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.5721C>T	p.Gly1907Gly	synonymous_variant	33/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.5703C>T	p.Gly1901Gly	synonymous_variant	31/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.5682C>T	p.Gly1894Gly	synonymous_variant	33/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1959C>T	p.Gly653Gly	synonymous_variant	15/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1944C>T	p.Gly648Gly	synonymous_variant	16/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1926C>T	p.Gly642Gly	synonymous_variant	15/17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*802C>T		non_coding_transcript_exon_variant	33/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3572C>T		non_coding_transcript_exon_variant	33/35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*802C>T		3_prime_UTR_variant	33/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*3572C>T		3_prime_UTR_variant	33/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.0942 AC: 14327 AN: 152052 Hom.: 921 Cov.: 34

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0739

Gnomad ASJ AF: 0.0844

Gnomad EAS AF: 0.0230

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.0986

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.0947

GnomAD3 exomes AF: 0.117 AC: 18331 AN: 156264 Hom.: 1478 AF XY: 0.129 AC XY: 10700 AN XY: 83042

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.0542

Gnomad ASJ exome AF: 0.0928

Gnomad EAS exome AF: 0.0243

Gnomad SAS exome AF: 0.240

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.131 AC: 183551 AN: 1399574 Hom.: 13304 Cov.: 35 AF XY: 0.135 AC XY: 93022 AN XY: 690564

Gnomad4 AFR exome AF: 0.0235

Gnomad4 AMR exome AF: 0.0566

Gnomad4 ASJ exome AF: 0.0915

Gnomad4 EAS exome AF: 0.0171

Gnomad4 SAS exome AF: 0.236

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.0941 AC: 14321 AN: 152170 Hom.: 919 Cov.: 34 AF XY: 0.0944 AC XY: 7020 AN XY: 74378

Gnomad4 AFR AF: 0.0273

Gnomad4 AMR AF: 0.0738

Gnomad4 ASJ AF: 0.0844

Gnomad4 EAS AF: 0.0227

Gnomad4 SAS AF: 0.245

Gnomad4 FIN AF: 0.0986

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.0942

Alfa AF: 0.119 Hom.: 384

Bravo AF: 0.0842

Asia WGS AF: 0.127 AC: 443 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.50
DANN	Benign	0.73

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: rs2738891; hg19: chr16-1268485; COSMIC: COSV52353392; COSMIC: COSV52353392;