chr3-130894533-C-T

Variant names:

• chr3-130894533-C-T
• rs115940289
• ENST00000328560.12:c.-237C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000328560.12(ATP2C1):​c.-237C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00652 in 1,393,578 control chromosomes in the GnomAD database, including 355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (205 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (150 hom.)
• Consequence: ATP2C1 ENST00000328560.12 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.447
• Publications: 0 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0934 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000328560.12. 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
	ATP2C1	NM_001378687.1	MANE Select	c.-180-57C>T		intron	N/A	NP_001365616.1	P98194-1
	ATP2C1	NM_001378511.1		c.109-35883C>T		intron	N/A	NP_001365440.1
	ATP2C1	NM_001199180.2		c.109-35883C>T		intron	N/A	NP_001186109.1	P98194-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2C1	ENST00000328560.12	TSL:1	c.-237C>T		5_prime_UTR	Exon 1 of 27	ENSP00000329664.8	P98194-2
	ATP2C1	ENST00000510168.6	TSL:5 MANE Select	c.-180-57C>T		intron	N/A	ENSP00000427461.1	P98194-1
	ATP2C1	ENST00000513801.5	TSL:1	c.-43+196C>T		intron	N/A	ENSP00000422872.1	P98194-3

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4420 AN: 151686 Hom.: 204 Cov.: 31

Gnomad AFR AF: 0.0961

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000845

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.0235

GnomAD4 exome AF: 0.00376 AC: 4670 AN: 1241778 Hom.: 150 Cov.: 33 AF XY: 0.00348 AC XY: 2086 AN XY: 599900

African (AFR) AF: 0.0963 AC: 2600 AN: 26990

American (AMR) AF: 0.0116 AC: 210 AN: 18172

Ashkenazi Jewish (ASJ) AF: 0.0223 AC: 397 AN: 17782

East Asian (EAS) AF: 0.00 AC: 0 AN: 32260

South Asian (SAS) AF: 0.000453 AC: 26 AN: 57438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27216

Middle Eastern (MID) AF: 0.0171 AC: 58 AN: 3394

European-Non Finnish (NFE) AF: 0.000904 AC: 911 AN: 1007374

Other (OTH) AF: 0.00915 AC: 468 AN: 51152

GnomAD4 genome AF: 0.0291 AC: 4423 AN: 151800 Hom.: 205 Cov.: 31 AF XY: 0.0288 AC XY: 2133 AN XY: 74174

African (AFR) AF: 0.0959 AC: 3967 AN: 41378

American (AMR) AF: 0.0141 AC: 216 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000634 AC: 3 AN: 4732

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10588

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00138 AC: 94 AN: 67914

Other (OTH) AF: 0.0232 AC: 49 AN: 2110

Alfa AF: 0.00689 Hom.: 5

Bravo AF: 0.0329

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial benign pemphigus (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		0.45
PromoterAI		-0.0099	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs115940289; hg19: chr3-130613377;