rs4247094

Variant names:

• chr16-1220349-T-C
• rs4247094
• ENST00000711482.1:c.6310T>C
• CACNA1H p.Cys2104Arg

Your query was ambiguous. Multiple possible variants found:

• chr16-1220349-T-C
• chr16-1220349-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000711482.1(CACNA1H):​c.6310T>C​(p.Cys2104Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.827 in 1,530,922 control chromosomes in the GnomAD database, including 525,248 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2104Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.86 (56213 hom., cov: 36)
  • Exomes 𝑓: 0.82 (469035 hom.)
• Consequence: CACNA1H ENST00000711482.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.557
• Publications: 17 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: G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.9).
• BP6: Variant 16-1220349-T-C is Benign according to our data. Variant chr16-1220349-T-C is described in ClinVar as Benign. ClinVar VariationId is 96018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

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.6417T>C	p.Asp2139Asp	synonymous	Exon 35 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.6399T>C	p.Asp2133Asp	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.6310T>C	p.Cys2104Arg	missense	Exon 36 of 36	ENSP00000518771.1	A0AAA9YHY2
	CACNA1H	ENST00000711485.1		c.6259T>C	p.Cys2087Arg	missense	Exon 35 of 35	ENSP00000518774.1	A0AAA9YHI7
	CACNA1H	ENST00000711455.1		c.6232T>C	p.Cys2078Arg	missense	Exon 36 of 36	ENSP00000518768.1	A0AAA9YHS9

Frequencies

GnomAD3 genomes AF: 0.858 AC: 130447 AN: 152124 Hom.: 56149 Cov.: 36

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.860

Gnomad ASJ AF: 0.903

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.933

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.806

Gnomad OTH AF: 0.862

GnomAD2 exomes AF: 0.858 AC: 141229 AN: 164594 AF XY: 0.856

Gnomad AFR exome AF: 0.903

Gnomad AMR exome AF: 0.870

Gnomad ASJ exome AF: 0.889

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.852

Gnomad NFE exome AF: 0.807

Gnomad OTH exome AF: 0.848

GnomAD4 exome AF: 0.823 AC: 1135149 AN: 1378680 Hom.: 469035 Cov.: 73 AF XY: 0.826 AC XY: 561774 AN XY: 680500

African (AFR) AF: 0.916 AC: 26782 AN: 29242

American (AMR) AF: 0.865 AC: 27924 AN: 32290

Ashkenazi Jewish (ASJ) AF: 0.896 AC: 19504 AN: 21760

East Asian (EAS) AF: 0.999 AC: 37153 AN: 37182

South Asian (SAS) AF: 0.922 AC: 69775 AN: 75678

European-Finnish (FIN) AF: 0.855 AC: 35503 AN: 41542

Middle Eastern (MID) AF: 0.904 AC: 4892 AN: 5412

European-Non Finnish (NFE) AF: 0.802 AC: 865588 AN: 1078724

Other (OTH) AF: 0.845 AC: 48028 AN: 56850

GnomAD4 genome AF: 0.858 AC: 130571 AN: 152242 Hom.: 56213 Cov.: 36 AF XY: 0.862 AC XY: 64187 AN XY: 74440

African (AFR) AF: 0.909 AC: 37779 AN: 41582

American (AMR) AF: 0.860 AC: 13150 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 3132 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5146 AN: 5152

South Asian (SAS) AF: 0.932 AC: 4502 AN: 4828

European-Finnish (FIN) AF: 0.865 AC: 9190 AN: 10620

Middle Eastern (MID) AF: 0.894 AC: 261 AN: 292

European-Non Finnish (NFE) AF: 0.806 AC: 54813 AN: 67978

Other (OTH) AF: 0.864 AC: 1829 AN: 2116

Alfa AF: 0.834 Hom.: 16300

Bravo AF: 0.858

Asia WGS AF: 0.962 AC: 3340 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Epilepsy, childhood absence, susceptibility to, 6 (2)
-	-	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	-0.90
CADD	Benign	0.22
DANN	Benign	0.44
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4247094;

hg19: chr16-1270349;

COSMIC: COSV52353255;

COSMIC: COSV52353255;