3-130894533-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000328560.12(ATP2C1):​c.-237C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000644 in 1,241,794 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: ATP2C1 ENST00000328560.12 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).

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>G		intron	N/A	NP_001365616.1	P98194-1
	ATP2C1	NM_001378511.1		c.109-35883C>G		intron	N/A	NP_001365440.1
	ATP2C1	NM_001199180.2		c.109-35883C>G		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>G		5_prime_UTR	Exon 1 of 27	ENSP00000329664.8	P98194-2
	ATP2C1	ENST00000510168.6	TSL:5 MANE Select	c.-180-57C>G		intron	N/A	ENSP00000427461.1	P98194-1
	ATP2C1	ENST00000513801.5	TSL:1	c.-43+196C>G		intron	N/A	ENSP00000422872.1	P98194-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000644 AC: 8 AN: 1241794 Hom.: 0 Cov.: 33 AF XY: 0.00000667 AC XY: 4 AN XY: 599902

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27006

American (AMR) AF: 0.00 AC: 0 AN: 18172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17784

East Asian (EAS) AF: 0.0000310 AC: 1 AN: 32260

South Asian (SAS) AF: 0.0000174 AC: 1 AN: 57438

European-Finnish (FIN) AF: 0.000110 AC: 3 AN: 27216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3394

European-Non Finnish (NFE) AF: 0.00000298 AC: 3 AN: 1007370

Other (OTH) AF: 0.00 AC: 0 AN: 51154

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00133300), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 5

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.79
PhyloP100		0.45
PromoterAI		-0.024	Neutral

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;