NM_001378687.1:c.117+7G>A

Variant names:

• chr3-130930533-G-A
• rs41266501
• NM_001378687.1:c.117+7G>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.117+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,560,120 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (26 hom.)
• Consequence: ATP2C1 NM_001378687.1 splice_region, intron
• Scores: Splicing: ADA: 0.0001135
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.740
• 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 (BayesDel_noAF=-0.69).
• BP6: Variant 3-130930533-G-A is Benign according to our data. Variant chr3-130930533-G-A is described in ClinVar as Benign. ClinVar VariationId is 343318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00335 (510/152246) while in subpopulation AMR AF = 0.00701 (107/15272). AF 95% confidence interval is 0.00593. There are 2 homozygotes in GnomAd4. There are 242 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 510 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.117+7G>A		splice_region intron	N/A	NP_001365616.1	P98194-1
	ATP2C1	NM_001378511.1		c.219+7G>A		splice_region intron	N/A	NP_001365440.1
	ATP2C1	NM_001199180.2		c.219+7G>A		splice_region 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.117+7G>A		splice_region intron	N/A	ENSP00000427461.1	P98194-1
	ATP2C1	ENST00000359644.7	TSL:1	c.117+7G>A		splice_region intron	N/A	ENSP00000352665.3	P98194-9
	ATP2C1	ENST00000422190.6	TSL:1	c.117+7G>A		splice_region intron	N/A	ENSP00000402677.2	P98194-5

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 510 AN: 152128 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00702

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00487

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00330 AC: 824 AN: 249964 AF XY: 0.00339

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00460

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00453

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00441 AC: 6210 AN: 1407874 Hom.: 26 Cov.: 24 AF XY: 0.00437 AC XY: 3071 AN XY: 703476

African (AFR) AF: 0.000866 AC: 28 AN: 32342

American (AMR) AF: 0.00468 AC: 209 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00128 AC: 33 AN: 25808

East Asian (EAS) AF: 0.00 AC: 0 AN: 39416

South Asian (SAS) AF: 0.00218 AC: 186 AN: 85148

European-Finnish (FIN) AF: 0.00180 AC: 96 AN: 53372

Middle Eastern (MID) AF: 0.00141 AC: 8 AN: 5676

European-Non Finnish (NFE) AF: 0.00515 AC: 5472 AN: 1062892

Other (OTH) AF: 0.00304 AC: 178 AN: 58572

GnomAD4 genome AF: 0.00335 AC: 510 AN: 152246 Hom.: 2 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74454

African (AFR) AF: 0.000890 AC: 37 AN: 41572

American (AMR) AF: 0.00701 AC: 107 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00487 AC: 331 AN: 68000

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00352 Hom.: 1

Bravo AF: 0.00335

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00504

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.7
DANN	Benign	0.52
PhyloP100		0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0020
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: rs41266501; hg19: chr3-130649377;