chr16-84459285-G-A

Variant names:

• chr16-84459285-G-A
• rs188467730
• NM_014861.4:c.2232G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014861.4(ATP2C2):​c.2232G>A​(p.Leu744Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000942 in 1,614,186 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (7 hom.)
• Consequence: ATP2C2 NM_014861.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.845
• Publications: 2 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)

ENSG00000305404 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 16-84459285-G-A is Benign according to our data. Variant chr16-84459285-G-A is described in ClinVar as Benign. ClinVar VariationId is 718293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.845 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00525 (799/152326) while in subpopulation AFR AF = 0.0183 (762/41566). AF 95% confidence interval is 0.0173. There are 9 homozygotes in GnomAd4. There are 362 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014861.4. 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
	ATP2C2	NM_014861.4	MANE Select	c.2232G>A	p.Leu744Leu	synonymous	Exon 23 of 27	NP_055676.3	O75185-1
	ATP2C2	NM_001286527.3		c.2232G>A	p.Leu744Leu	synonymous	Exon 23 of 28	NP_001273456.2	O75185-3
	ATP2C2	NM_001291454.2		c.1779G>A	p.Leu593Leu	synonymous	Exon 20 of 24	NP_001278383.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2C2	ENST00000262429.9	TSL:1 MANE Select	c.2232G>A	p.Leu744Leu	synonymous	Exon 23 of 27	ENSP00000262429.4	O75185-1
	ATP2C2	ENST00000416219.7	TSL:1	c.2232G>A	p.Leu744Leu	synonymous	Exon 23 of 28	ENSP00000397925.2
	ATP2C2-AS1	ENST00000565700.1	TSL:1	n.2972C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 799 AN: 152208 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

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: 0.00239

GnomAD2 exomes AF: 0.00131 AC: 327 AN: 249512 AF XY: 0.000857

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000494 AC: 722 AN: 1461860 Hom.: 7 Cov.: 36 AF XY: 0.000411 AC XY: 299 AN XY: 727232

African (AFR) AF: 0.0171 AC: 571 AN: 33478

American (AMR) AF: 0.00103 AC: 46 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1112006

Other (OTH) AF: 0.00116 AC: 70 AN: 60396

GnomAD4 genome AF: 0.00525 AC: 799 AN: 152326 Hom.: 9 Cov.: 33 AF XY: 0.00486 AC XY: 362 AN XY: 74488

African (AFR) AF: 0.0183 AC: 762 AN: 41566

American (AMR) AF: 0.00196 AC: 30 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00191 Hom.: 3

Bravo AF: 0.00589

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ATP2C2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		0.84
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs188467730; hg19: chr16-84492891;