chr16-1220511-G-A

Position:

• chr16-1220511-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021098.3(CACNA1H):​c.6579G>A​(p.Ser2193Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,540,164 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (42 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.10

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-1220511-G-A is Benign according to our data. Variant chr16-1220511-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 529679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00115 (175/152210) while in subpopulation SAS AF= 0.0234 (113/4830). AF 95% confidence interval is 0.0199. There are 3 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 175 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6579G>A	p.Ser2193Ser	synonymous_variant	35/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6579G>A	p.Ser2193Ser	synonymous_variant	35/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.6561G>A	p.Ser2187Ser	synonymous_variant	33/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.6540G>A	p.Ser2180Ser	synonymous_variant	35/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.2817G>A	p.Ser939Ser	synonymous_variant	17/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.2769G>A	p.Ser923Ser	synonymous_variant	18/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.2751G>A	p.Ser917Ser	synonymous_variant	17/17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*1627G>A		non_coding_transcript_exon_variant	35/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4397G>A		non_coding_transcript_exon_variant	35/35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*1627G>A		3_prime_UTR_variant	35/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4397G>A		3_prime_UTR_variant	35/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152092 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00302 AC: 511 AN: 169188 Hom.: 11 AF XY: 0.00342 AC XY: 316 AN XY: 92394

Gnomad AFR exome AF: 0.0000771

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000795

Gnomad SAS exome AF: 0.0237

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.000819

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00159 AC: 2202 AN: 1387954 Hom.: 42 Cov.: 35 AF XY: 0.00208 AC XY: 1428 AN XY: 685714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00551

Gnomad4 SAS exome AF: 0.0214

Gnomad4 FIN exome AF: 0.00225

Gnomad4 NFE exome AF: 0.000161

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152210 Hom.: 3 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74422

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00310

Gnomad4 SAS AF: 0.0234

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000424 Hom.: 0

Bravo AF: 0.000276

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 22, 2024

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 23, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.26
DANN	Benign	0.88

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: rs200017975; hg19: chr16-1270511;