rs61731516

Variant names:

• chr3-130979301-G-C
• rs61731516
• NM_001378687.1:c.1623G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-130979301-G-C
• chr3-130979301-G-A

Variant summary

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

The NM_001378687.1(ATP2C1):​c.1623G>C​(p.Leu541Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000847 in 1,613,532 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (6 hom.)
• Consequence: ATP2C1 NM_001378687.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.99
• Publications: 1 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 (MetaRNN=0.013946325).
• BP6: Variant 3-130979301-G-C is Benign according to our data. Variant chr3-130979301-G-C is described in ClinVar as Benign. ClinVar VariationId is 377375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00469 (714/152094) while in subpopulation AFR AF = 0.0157 (650/41472). AF 95% confidence interval is 0.0147. There are 5 homozygotes in GnomAd4. There are 326 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 714 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2C1	NM_001378687.1	MANE Select	c.1623G>C	p.Leu541Phe	missense	Exon 19 of 28	NP_001365616.1	P98194-1
	ATP2C1	NM_001378511.1		c.1725G>C	p.Leu575Phe	missense	Exon 18 of 28	NP_001365440.1
	ATP2C1	NM_001199180.2		c.1725G>C	p.Leu575Phe	missense	Exon 18 of 28	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.1623G>C	p.Leu541Phe	missense	Exon 19 of 28	ENSP00000427461.1	P98194-1
	ATP2C1	ENST00000359644.7	TSL:1	c.1623G>C	p.Leu541Phe	missense	Exon 18 of 28	ENSP00000352665.3	P98194-9
	ATP2C1	ENST00000422190.6	TSL:1	c.1623G>C	p.Leu541Phe	missense	Exon 18 of 28	ENSP00000402677.2	P98194-5

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 715 AN: 151976 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00124 AC: 311 AN: 251006 AF XY: 0.000877

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.000724

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000447 AC: 653 AN: 1461438 Hom.: 6 Cov.: 31 AF XY: 0.000362 AC XY: 263 AN XY: 727022

African (AFR) AF: 0.0164 AC: 547 AN: 33450

American (AMR) AF: 0.000828 AC: 37 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111732

Other (OTH) AF: 0.000977 AC: 59 AN: 60380

GnomAD4 genome AF: 0.00469 AC: 714 AN: 152094 Hom.: 5 Cov.: 32 AF XY: 0.00438 AC XY: 326 AN XY: 74366

African (AFR) AF: 0.0157 AC: 650 AN: 41472

American (AMR) AF: 0.00295 AC: 45 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68004

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.000406 Hom.: 0

Bravo AF: 0.00543

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00155 AC: 188

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ATP2C1-related disorder (1)
-	-	1	Familial benign pemphigus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.67
Sift	Benign	0.12	T
Sift4G	Benign	0.075	T
Polyphen		0.61	P
Vest4		0.88
MutPred		0.69		Gain of sheet (P = 0.1539)
MVP		0.83
ClinPred		0.030	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.83
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61731516; hg19: chr3-130698145;