rs57105517

Variant names:

• chr16-1211550-C-T
• rs57105517
• NM_021098.3:c.4420C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-1211550-C-T
• chr16-1211550-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_021098.3(CACNA1H):​c.4420C>T​(p.Arg1474Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000399 in 1,612,216 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: CACNA1H NM_021098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.669
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011384606).
• BP6: Variant 16-1211550-C-T is Benign according to our data. Variant chr16-1211550-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446953.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00191 (291/152332) while in subpopulation AFR AF = 0.00664 (276/41584). AF 95% confidence interval is 0.00599. There are 0 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 291 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. 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.4420C>T	p.Arg1474Trp	missense	Exon 23 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.4420C>T	p.Arg1474Trp	missense	Exon 23 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.4420C>T	p.Arg1474Trp	missense	Exon 23 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.4420C>T	p.Arg1474Trp	missense	Exon 23 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.4456C>T	p.Arg1486Trp	missense	Exon 23 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00666

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000536 AC: 132 AN: 246262 AF XY: 0.000365

Gnomad AFR exome AF: 0.00740

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000630

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000242 AC: 353 AN: 1459884 Hom.: 1 Cov.: 35 AF XY: 0.000205 AC XY: 149 AN XY: 726222

African (AFR) AF: 0.00816 AC: 273 AN: 33458

American (AMR) AF: 0.000358 AC: 16 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86228

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52060

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111602

Other (OTH) AF: 0.000481 AC: 29 AN: 60332

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.00177 AC XY: 132 AN XY: 74484

African (AFR) AF: 0.00664 AC: 276 AN: 41584

American (AMR) AF: 0.000849 AC: 13 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000655 Hom.: 1

Bravo AF: 0.00234

ESP6500AA AF: 0.00623 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000655 AC: 79

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.17	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.1	L
PhyloP100		-0.67
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.39
Sift	Benign	0.11	T
Sift4G	Benign	0.071	T
Polyphen		0.99	D
Vest4		0.36
MVP		0.75
ClinPred		0.0062	T
GERP RS		-1.7
Varity_R		0.050
gMVP		0.64
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs57105517; hg19: chr16-1261550;