NM_001378687.1:c.6+15C>G

Variant names:

• chr3-130894790-C-G
• rs112703671
• NM_001378687.1:c.6+15C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378687.1(ATP2C1):​c.6+15C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0667 in 1,613,022 control chromosomes in the GnomAD database, including 4,126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (263 hom., cov: 31)
  • Exomes 𝑓: 0.069 (3863 hom.)
• Consequence: ATP2C1 NM_001378687.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0540
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-130894790-C-G is Benign according to our data. Variant chr3-130894790-C-G is described in ClinVar as Benign. ClinVar VariationId is 343317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0755 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2C1	NM_001378687.1	MANE Select	c.6+15C>G		intron	N/A	NP_001365616.1	P98194-1
	ATP2C1	NM_001378511.1		c.109-35626C>G		intron	N/A	NP_001365440.1
	ATP2C1	NM_001199180.2		c.109-35626C>G		intron	N/A	NP_001186109.1	P98194-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2C1	ENST00000510168.6	TSL:5 MANE Select	c.6+15C>G		intron	N/A	ENSP00000427461.1	P98194-1
	ATP2C1	ENST00000359644.7	TSL:1	c.6+15C>G		intron	N/A	ENSP00000352665.3	P98194-9
	ATP2C1	ENST00000422190.6	TSL:1	c.6+15C>G		intron	N/A	ENSP00000402677.2	P98194-5

Frequencies

GnomAD3 genomes AF: 0.0495 AC: 7531 AN: 152162 Hom.: 263 Cov.: 31

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.0644

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0772

Gnomad OTH AF: 0.0498

GnomAD2 exomes AF: 0.0500 AC: 12568 AN: 251414 AF XY: 0.0505

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.0302

Gnomad ASJ exome AF: 0.0396

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0635

Gnomad NFE exome AF: 0.0759

Gnomad OTH exome AF: 0.0513

GnomAD4 exome AF: 0.0685 AC: 100133 AN: 1460742 Hom.: 3863 Cov.: 32 AF XY: 0.0673 AC XY: 48877 AN XY: 726786

African (AFR) AF: 0.0107 AC: 357 AN: 33464

American (AMR) AF: 0.0312 AC: 1394 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0382 AC: 998 AN: 26132

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39698

South Asian (SAS) AF: 0.0205 AC: 1767 AN: 86236

European-Finnish (FIN) AF: 0.0640 AC: 3420 AN: 53414

Middle Eastern (MID) AF: 0.0252 AC: 145 AN: 5764

European-Non Finnish (NFE) AF: 0.0797 AC: 88570 AN: 1110956

Other (OTH) AF: 0.0576 AC: 3476 AN: 60356

GnomAD4 genome AF: 0.0494 AC: 7530 AN: 152280 Hom.: 263 Cov.: 31 AF XY: 0.0478 AC XY: 3557 AN XY: 74462

African (AFR) AF: 0.0131 AC: 546 AN: 41556

American (AMR) AF: 0.0455 AC: 697 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 133 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0188 AC: 91 AN: 4830

European-Finnish (FIN) AF: 0.0644 AC: 683 AN: 10604

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0772 AC: 5253 AN: 68014

Other (OTH) AF: 0.0497 AC: 105 AN: 2112

Alfa AF: 0.0597 Hom.: 67

Bravo AF: 0.0467

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Familial benign pemphigus (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	14
DANN	Benign	0.65
PhyloP100		-0.054
PromoterAI		-0.026	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs112703671; hg19: chr3-130613634;