3-130850882-T-A

Variant names:

• chr3-130850882-T-A
• rs554783338
• NM_001378511.1:c.62T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001378511.1(ATP2C1):​c.62T>A​(p.Ile21Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000288 in 1,424,734 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: ATP2C1 NM_001378511.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.89

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]

LOC107986023 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010445058).
• BP6: Variant 3-130850882-T-A is Benign according to our data. Variant chr3-130850882-T-A is described in ClinVar as [Benign]. Clinvar id is 3035209.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00146 (222/152326) while in subpopulation AFR AF = 0.005 (208/41560). AF 95% confidence interval is 0.00445. There are 2 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 222 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2C1	NM_001378511.1	c.62T>A	p.Ile21Asn	missense_variant	Exon 1 of 28		NP_001365440.1
ATP2C1	NM_001199180.2	c.62T>A	p.Ile21Asn	missense_variant	Exon 1 of 28		NP_001186109.1
ATP2C1	NM_001199181.3	c.62T>A	p.Ile21Asn	missense_variant	Exon 1 of 27		NP_001186110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2C1	ENST00000507488.6	c.62T>A	p.Ile21Asn	missense_variant	Exon 1 of 28	2		ENSP00000421326.3
ATP2C1	ENST00000505330.5	c.62T>A	p.Ile21Asn	missense_variant	Exon 1 of 27	2		ENSP00000423774.2
ATP2C1	ENST00000504381.5	c.62T>A	p.Ile21Asn	missense_variant	Exon 1 of 27	2		ENSP00000425320.2
ATP2C1	ENST00000509150.1	n.100T>A		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152208 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00504

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000180 AC: 11 AN: 61204 AF XY: 0.000141

Gnomad AFR exome AF: 0.00407

Gnomad AMR exome AF: 0.000226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000400

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000149 AC: 189 AN: 1272408 Hom.: 2 Cov.: 28 AF XY: 0.000141 AC XY: 88 AN XY: 624140

Gnomad4 AFR exome AF: 0.00561 AC: 149 AN: 26570

Gnomad4 AMR exome AF: 0.000445 AC: 9 AN: 20206

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 21430

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 30462

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 58396

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 30888

Gnomad4 NFE exome AF: 0.00000292 AC: 3 AN: 1026246

Gnomad4 Remaining exome AF: 0.000529 AC: 28 AN: 52954

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.00134 AC XY: 100 AN XY: 74496

Gnomad4 AFR AF: 0.00500 AC: 0.00500481 AN: 0.00500481

Gnomad4 AMR AF: 0.000654 AC: 0.000653509 AN: 0.000653509

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000293988 AN: 0.0000293988

Gnomad4 OTH AF: 0.000945 AC: 0.00094518 AN: 0.00094518

Alfa AF: 0.000898 Hom.: 0

Bravo AF: 0.00177

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ATP2C1-related disorder Benign:1

Mar 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0074	T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.058
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.35	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.28	N;N;N
Sift	Benign	0.44	T;D;T
Sift4G	Benign	0.31	T;D;T
Polyphen		0.0020	B;.;.
Vest4		0.54
MVP		0.75
ClinPred		0.044	T
GERP RS		6.0
gMVP		0.35
Mutation Taster		=86/14	polymorphism

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs554783338; hg19: chr3-130569726;