16-1220166-C-T

Variant names:

• chr16-1220166-C-T
• rs59844753
• ENST00000711482.1:c.6127C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000711482.1(CACNA1H):​c.6127C>T​(p.Arg2043Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,520,138 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2043G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0087 (10 hom., cov: 35)
  • Exomes 𝑓: 0.012 (126 hom.)
• Consequence: CACNA1H ENST00000711482.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.72
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 16-1220166-C-T is Benign according to our data. Variant chr16-1220166-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00869 (1323/152330) while in subpopulation NFE AF = 0.014 (949/68010). AF 95% confidence interval is 0.0132. There are 10 homozygotes in GnomAd4. There are 576 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1323 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000711482.1. 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.6234C>T	p.Cys2078Cys	synonymous	Exon 35 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.6216C>T	p.Cys2072Cys	synonymous	Exon 34 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000711482.1		c.6127C>T	p.Arg2043Cys	missense	Exon 36 of 36	ENSP00000518771.1	A0AAA9YHY2
	CACNA1H	ENST00000711485.1		c.6076C>T	p.Arg2026Cys	missense	Exon 35 of 35	ENSP00000518774.1	A0AAA9YHI7
	CACNA1H	ENST00000711455.1		c.6049C>T	p.Arg2017Cys	missense	Exon 36 of 36	ENSP00000518768.1	A0AAA9YHS9

Frequencies

GnomAD3 genomes AF: 0.00869 AC: 1323 AN: 152212 Hom.: 10 Cov.: 35

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.00876

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.00947 AC: 1528 AN: 161270 AF XY: 0.00939

Gnomad AFR exome AF: 0.00270

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.000422

Gnomad FIN exome AF: 0.00221

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.0119 AC: 16236 AN: 1367808 Hom.: 126 Cov.: 72 AF XY: 0.0115 AC XY: 7738 AN XY: 673204

African (AFR) AF: 0.00160 AC: 45 AN: 28070

American (AMR) AF: 0.00970 AC: 312 AN: 32162

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 255 AN: 21028

East Asian (EAS) AF: 0.000113 AC: 4 AN: 35528

South Asian (SAS) AF: 0.00247 AC: 178 AN: 71974

European-Finnish (FIN) AF: 0.00275 AC: 133 AN: 48282

Middle Eastern (MID) AF: 0.0108 AC: 58 AN: 5362

European-Non Finnish (NFE) AF: 0.0137 AC: 14677 AN: 1069114

Other (OTH) AF: 0.0102 AC: 574 AN: 56288

GnomAD4 genome AF: 0.00869 AC: 1323 AN: 152330 Hom.: 10 Cov.: 35 AF XY: 0.00773 AC XY: 576 AN XY: 74486

African (AFR) AF: 0.00265 AC: 110 AN: 41584

American (AMR) AF: 0.00875 AC: 134 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4832

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10628

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0140 AC: 949 AN: 68010

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.00780 Hom.: 16

Bravo AF: 0.00889

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.0
DANN	Benign	0.90
PhyloP100		-1.7
Mutation Taster		=99/1	polymorphism

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: rs59844753; hg19: chr16-1270166; COSMIC: COSV52353423; COSMIC: COSV52353423;