ENST00000428331.6:c.-213C>A

Variant names:

• chr3-130894557-C-A
• rs181664730
• ENST00000428331.6:c.-213C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000428331.6(ATP2C1):​c.-213C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,425,194 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0054 (24 hom.)
• Consequence: ATP2C1 ENST00000428331.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.675
• 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: PanelApp Australia, Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 3-130894557-C-A is Benign according to our data. Variant chr3-130894557-C-A is described in ClinVar as Benign. ClinVar VariationId is 343313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00429 (653/152152) while in subpopulation NFE AF = 0.00669 (455/67982). AF 95% confidence interval is 0.00618. There are 2 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 653 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000428331.6. 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.-180-33C>A		intron	N/A	NP_001365616.1	P98194-1
	ATP2C1	NM_014382.5		c.-213C>A		5_prime_UTR	Exon 1 of 27	NP_055197.2
	ATP2C1	NM_001199185.2		c.-213C>A		5_prime_UTR	Exon 1 of 27	NP_001186114.1	P98194-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2C1	ENST00000428331.6	TSL:1	c.-213C>A		5_prime_UTR	Exon 1 of 27	ENSP00000395809.2	P98194-1
	ATP2C1	ENST00000328560.12	TSL:1	c.-213C>A		5_prime_UTR	Exon 1 of 27	ENSP00000329664.8	P98194-2
	ATP2C1	ENST00000510168.6	TSL:5 MANE Select	c.-180-33C>A		intron	N/A	ENSP00000427461.1	P98194-1

Frequencies

GnomAD3 genomes AF: 0.00430 AC: 653 AN: 152034 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00669

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00537 AC: 6840 AN: 1273042 Hom.: 24 Cov.: 33 AF XY: 0.00546 AC XY: 3374 AN XY: 617692

African (AFR) AF: 0.000822 AC: 23 AN: 27966

American (AMR) AF: 0.00188 AC: 39 AN: 20700

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 203 AN: 18688

East Asian (EAS) AF: 0.00 AC: 0 AN: 33724

South Asian (SAS) AF: 0.00275 AC: 170 AN: 61930

European-Finnish (FIN) AF: 0.00287 AC: 91 AN: 31656

Middle Eastern (MID) AF: 0.00650 AC: 23 AN: 3538

European-Non Finnish (NFE) AF: 0.00589 AC: 6023 AN: 1022228

Other (OTH) AF: 0.00509 AC: 268 AN: 52612

GnomAD4 genome AF: 0.00429 AC: 653 AN: 152152 Hom.: 2 Cov.: 31 AF XY: 0.00402 AC XY: 299 AN XY: 74374

African (AFR) AF: 0.00125 AC: 52 AN: 41534

American (AMR) AF: 0.00157 AC: 24 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4806

European-Finnish (FIN) AF: 0.00255 AC: 27 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00669 AC: 455 AN: 67982

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00229 Hom.: 0

Bravo AF: 0.00417

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

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	-0.65
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		-0.68
PromoterAI		-0.093	Neutral
Mutation Taster		=283/17	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs181664730; hg19: chr3-130613401;