Genetic Variant ATP2C1:p.Ile21Asn (chr3-130850882-T-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001378511.1(ATP2C1):c.62T>A(p.Ile21Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000288 in 1,424,734 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 2 hom. )

Consequence

ATP2C1
NM_001378511.1 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.89

Publications

0 publications found

Variant links:

Genes affected

ATP2C1 (HGNC:13211): (ATPase secretory pathway Ca2+ transporting 1) The protein encoded by this gene belongs to the family of P-type cation transport ATPases. This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the transport of calcium ions. Defects in this gene cause Hailey-Hailey disease, an autosomal dominant disorder. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

ATP2C1 Gene-Disease associations (from GenCC):

Hailey-Hailey disease
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ATP2C1 links:

ENSG00000306101 (HGNC:):

ENSG00000306101 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010445058).

BP6

Variant 3-130850882-T-A is Benign according to our data. Variant chr3-130850882-T-A is described in ClinVar as Benign. ClinVar VariationId is 3035209.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00146 (222/152326) while in subpopulation AFR AF = 0.005 (208/41560). AF 95% confidence interval is 0.00445. There are 2 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 222 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378511.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP2C1	NM_001378511.1	c.62T>A	p.Ile21Asn	missense	Exon 1 of 28	NP_001365440.1
ATP2C1	NM_001199180.2	c.62T>A	p.Ile21Asn	missense	Exon 1 of 28	NP_001186109.1	P98194-7
ATP2C1	NM_001199181.3	c.62T>A	p.Ile21Asn	missense	Exon 1 of 27	NP_001186110.1	B4E2Q0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP2C1	ENST00000507488.6	TSL:2	c.62T>A	p.Ile21Asn	missense	Exon 1 of 28	ENSP00000421326.3	P98194-7
ATP2C1	ENST00000505330.5	TSL:2	c.62T>A	p.Ile21Asn	missense	Exon 1 of 27	ENSP00000423774.2	B4E2Q0
ATP2C1	ENST00000504381.5	TSL:2	c.62T>A	p.Ile21Asn	missense	Exon 1 of 27	ENSP00000425320.2	P98194-8

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

223

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00504

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

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:

0.0000294

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000180

AC:

AN:

61204

AF XY:

0.000141

show subpopulations

Gnomad AFR exome

AF:

0.00407

Gnomad AMR exome

AF:

0.000226

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000400

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000149

AC:

189

AN:

1272408

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

624140

show subpopulations

African (AFR)

AF:

0.00561

AC:

149

AN:

26570

American (AMR)

AF:

0.000445

AC:

AN:

20206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21430

East Asian (EAS)

AF:

0.00

AC:

AN:

30462

South Asian (SAS)

AF:

0.00

AC:

AN:

58396

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30888

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5256

European-Non Finnish (NFE)

AF:

0.00000292

AC:

AN:

1026246

Other (OTH)

AF:

0.000529

AC:

AN:

52954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00146

AC:

222

AN:

152326

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00500

AC:

208

AN:

41560

American (AMR)

AF:

0.000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000898

Hom.:

Bravo

AF:

0.00177

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

ATP2C1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0074

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.058

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.35

PhyloP100

2.9

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.28

Sift

Benign

0.44

Sift4G

Benign

0.31

Polyphen

0.0020

Vest4

0.54

MVP

0.75

ClinPred

0.044

GERP RS

6.0

PromoterAI

-0.020

Neutral

(source)

gMVP

0.35

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over