chr16-84405153-A-T

Position:

• chr16-84405153-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_014861.4(ATP2C2):​c.236A>T​(p.Glu79Val) variant causes a missense change. The variant allele was found at a frequency of 0.00104 in 1,613,816 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: ATP2C2 NM_014861.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.72

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 16-84405153-A-T is Benign according to our data. Variant chr16-84405153-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2048303.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP2C2	NM_014861.4	c.236A>T	p.Glu79Val	missense_variant	3/27	ENST00000262429.9
ATP2C2	NM_001286527.3	c.236A>T	p.Glu79Val	missense_variant	3/28
ATP2C2	XM_011523486.3	c.167A>T	p.Glu56Val	missense_variant	3/28
ATP2C2	XM_047434994.1	c.167A>T	p.Glu56Val	missense_variant	3/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP2C2	ENST00000262429.9	c.236A>T	p.Glu79Val	missense_variant	3/27	1	NM_014861.4	P1
ATP2C2	ENST00000416219.6	c.236A>T	p.Glu79Val	missense_variant	3/28	1
ATP2C2	ENST00000565631.5	n.727A>T		non_coding_transcript_exon_variant	1/25	2

Frequencies

GnomAD3 genomes AF: 0.000665 AC: 101 AN: 151886 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000473

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000489 AC: 122 AN: 249524 Hom.: 0 AF XY: 0.000517 AC XY: 70 AN XY: 135370

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.000945

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.00107 AC: 1570 AN: 1461812 Hom.: 4 Cov.: 31 AF XY: 0.00105 AC XY: 766 AN XY: 727204

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.000664 AC: 101 AN: 152004 Hom.: 0 Cov.: 32 AF XY: 0.000606 AC XY: 45 AN XY: 74298

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000473

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000898 Hom.: 0

Bravo AF: 0.000559

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000237 AC: 1

ESP6500EA AF: 0.000472 AC: 4

ExAC AF: 0.000454 AC: 55

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00153

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.236A>T (p.E79V) alteration is located in exon 3 (coding exon 3) of the ATP2C2 gene. This alteration results from a A to T substitution at nucleotide position 236, causing the glutamic acid (E) at amino acid position 79 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.55
Sift	Benign	0.22	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.89	P;.
Vest4		0.71
MVP		0.72
ClinPred		0.059	T
GERP RS		5.1
Varity_R		0.16
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs201569578; hg19: chr16-84438759; COSMIC: COSV52294205; COSMIC: COSV52294205;