Genetic Variant ATP2C1:c.2243+108A>T (chr3-130996904-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001378687.1(ATP2C1):c.2243+108A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 814,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

ATP2C1
NM_001378687.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.35

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000197 (30/152230) while in subpopulation NFE AF = 0.000353 (24/67980). AF 95% confidence interval is 0.000243. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 30 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378687.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATP2C1	NM_001378687.1	MANE Select	c.2243+108A>T	intron	N/A	NP_001365616.1	P98194-1
ATP2C1	NM_001378511.1		c.2345+108A>T	intron	N/A	NP_001365440.1
ATP2C1	NM_001199180.2		c.2345+108A>T	intron	N/A	NP_001186109.1	P98194-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATP2C1	ENST00000510168.6	TSL:5 MANE Select	c.2243+108A>T	intron	N/A	ENSP00000427461.1	P98194-1
ATP2C1	ENST00000359644.7	TSL:1	c.2243+108A>T	intron	N/A	ENSP00000352665.3	P98194-9
ATP2C1	ENST00000422190.6	TSL:1	c.2243+108A>T	intron	N/A	ENSP00000402677.2	P98194-5

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000230

AC:

152

AN:

662126

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

357576

show subpopulations

African (AFR)

AF:

0.0000564

AC:

AN:

17744

American (AMR)

AF:

0.0000245

AC:

AN:

40818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20676

East Asian (EAS)

AF:

0.00

AC:

AN:

35814

South Asian (SAS)

AF:

0.00

AC:

AN:

67532

European-Finnish (FIN)

AF:

0.0000661

AC:

AN:

45388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4182

European-Non Finnish (NFE)

AF:

0.000351

AC:

139

AN:

395786

Other (OTH)

AF:

0.000234

AC:

AN:

34186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000197

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41562

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.00

Hom.:

2059

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.1

(source)

DANN

Benign

0.67

PhyloP100

-1.4

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

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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