chr16-84461712-A-C

Variant names:

• chr16-84461712-A-C
• rs4782970
• NM_014861.4:c.2482-2A>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PVS1_Moderate BP6_Very_Strong BS2

The NM_001286527.3(ATP2C2):​c.2569-2A>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_001286527.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 8.24
• Publications: 13 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.033811476 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 16-84461712-A-C is Benign according to our data. Variant chr16-84461712-A-C is described in ClinVar as Benign. ClinVar VariationId is 789227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286527.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2C2	NM_014861.4	MANE Select	c.2482-2A>C		splice_acceptor intron	N/A	NP_055676.3
	ATP2C2	NM_001286527.3		c.2569-2A>C		splice_acceptor intron	N/A	NP_001273456.2
	ATP2C2	NM_001291454.2		c.2029-2A>C		splice_acceptor intron	N/A	NP_001278383.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2C2	ENST00000262429.9	TSL:1 MANE Select	c.2482-2A>C		splice_acceptor intron	N/A	ENSP00000262429.4
	ATP2C2	ENST00000416219.7	TSL:1	c.2569-2A>C		splice_acceptor intron	N/A	ENSP00000397925.2
	ATP2C2-AS1	ENST00000565700.1	TSL:1	n.1346T>G		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1165 AN: 152194 Hom.: 12 Cov.: 33

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

GnomAD2 exomes AF: 0.00874 AC: 2181 AN: 249480 AF XY: 0.00912

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 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

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.00631 AC: 282 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00574 AC: 495 AN: 86236

European-Finnish (FIN) AF: 0.0224 AC: 1194 AN: 53420

Middle Eastern (MID) AF: 0.0127 AC: 73 AN: 5768

European-Non Finnish (NFE) AF: 0.00878 AC: 9764 AN: 1111652

Other (OTH) AF: 0.00836 AC: 505 AN: 60380

GnomAD4 genome AF: 0.00764 AC: 1164 AN: 152312 Hom.: 12 Cov.: 33 AF XY: 0.00838 AC XY: 624 AN XY: 74480

African (AFR) AF: 0.00171 AC: 71 AN: 41570

American (AMR) AF: 0.00588 AC: 90 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4828

European-Finnish (FIN) AF: 0.0273 AC: 290 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00978 AC: 665 AN: 68022

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00864 Hom.: 16

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ATP2C2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		8.2
GERP RS		5.3
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs4782970; hg19: chr16-84495318;