NM_014861.4:c.2482-2A>C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PVS1_ModeratePP3BP6_Very_StrongBS2

The NM_014861.4(ATP2C2):​c.2482-2A>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00838 in 1,613,792 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 12 hom., cov: 33)
Exomes 𝑓: 0.0085 ( 98 hom. )

Consequence

ATP2C2
NM_014861.4 splice_acceptor, intron

Scores

3
2
2
Splicing: ADA: 1.000
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 8.24
Variant links:
Genes affected
ATP2C2 (HGNC:29103): (ATPase secretory pathway Ca2+ transporting 2) Enables P-type calcium transporter activity and P-type manganese transporter activity. Predicted to be involved in calcium ion transmembrane transport; cellular calcium ion homeostasis; and manganese ion transport. Predicted to act upstream of or within mammary gland epithelium development; positive regulation of calcium ion import; and protein localization to plasma membrane. Predicted to be located in trans-Golgi network membrane. Predicted to be active in Golgi membrane; endoplasmic reticulum; and plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]
ATP2C2-AS1 (HGNC:53167): (ATP2C2 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.034846883 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PP3
Multiple lines of computational evidence support a deleterious effect 6: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen, phyloP100way_vertebrate [when BayesDel_addAF, MutationTaster was below the threshold]
BP6
Variant 16-84461712-A-C is Benign according to our data. Variant chr16-84461712-A-C is described in ClinVar as [Benign]. Clinvar id is 789227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP2C2NM_014861.4 linkc.2482-2A>C splice_acceptor_variant, intron_variant Intron 24 of 26 ENST00000262429.9 NP_055676.3 O75185-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP2C2ENST00000262429.9 linkc.2482-2A>C splice_acceptor_variant, intron_variant Intron 24 of 26 1 NM_014861.4 ENSP00000262429.4 O75185-1

Frequencies

GnomAD3 genomes
AF:
0.00765
AC:
1165
AN:
152194
Hom.:
12
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00171
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00559
Gnomad FIN
AF:
0.0273
Gnomad MID
AF:
0.0190
Gnomad NFE
AF:
0.00978
Gnomad OTH
AF:
0.00718
GnomAD3 exomes
AF:
0.00874
AC:
2181
AN:
249480
Hom.:
20
AF XY:
0.00912
AC XY:
1234
AN XY:
135344
show subpopulations
Gnomad AFR exome
AF:
0.000903
Gnomad AMR exome
AF:
0.00539
Gnomad ASJ exome
AF:
0.000596
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS exome
AF:
0.00578
Gnomad FIN exome
AF:
0.0258
Gnomad NFE exome
AF:
0.0104
Gnomad OTH exome
AF:
0.00990
GnomAD4 exome
AF:
0.00846
AC:
12361
AN:
1461480
Hom.:
98
Cov.:
33
AF XY:
0.00845
AC XY:
6147
AN XY:
727086
show subpopulations
Gnomad4 AFR exome
AF:
0.000956
Gnomad4 AMR exome
AF:
0.00631
Gnomad4 ASJ exome
AF:
0.000536
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00574
Gnomad4 FIN exome
AF:
0.0224
Gnomad4 NFE exome
AF:
0.00878
Gnomad4 OTH exome
AF:
0.00836
GnomAD4 genome
AF:
0.00764
AC:
1164
AN:
152312
Hom.:
12
Cov.:
33
AF XY:
0.00838
AC XY:
624
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.00171
Gnomad4 AMR
AF:
0.00588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00539
Gnomad4 FIN
AF:
0.0273
Gnomad4 NFE
AF:
0.00978
Gnomad4 OTH
AF:
0.00711
Alfa
AF:
0.00896
Hom.:
9
Bravo
AF:
0.00579
TwinsUK
AF:
0.00674
AC:
25
ALSPAC
AF:
0.00804
AC:
31
ESP6500AA
AF:
0.000927
AC:
4
ESP6500EA
AF:
0.00997
AC:
85
ExAC
AF:
0.00843
AC:
1022
Asia WGS
AF:
0.00289
AC:
10
AN:
3478
EpiCase
AF:
0.00851
EpiControl
AF:
0.0101

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Feb 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ATP2C2: BS1, BS2; ATP2C2-AS1: BS1, BS2 -

Dec 31, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

ATP2C2-related disorder Benign:1
Aug 31, 2020
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely 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
-0.11
T
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.3

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.73
Position offset: 12
DS_AL_spliceai
1.0
Position offset: 2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4782970; hg19: chr16-84495318; API