Genetic Variant NM_014861.4:c.41G>C (chr16-84368656-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014861.4(ATP2C2):c.41G>C(p.Gly14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,412,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G14D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

ATP2C2
NM_014861.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.814

Publications

0 publications found

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.037747175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2C2	NM_014861.4 link	c.41G>C	p.Gly14Ala	missense_variant	Exon 1 of 27	ENST00000262429.9	NP_055676.3	O75185-1
ATP2C2	NM_001286527.3 link	c.41G>C	p.Gly14Ala	missense_variant	Exon 1 of 28		NP_001273456.2	O75185-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2C2	ENST00000262429.9 link	c.41G>C	p.Gly14Ala	missense_variant	Exon 1 of 27	1	NM_014861.4	ENSP00000262429.4		O75185-1
ATP2C2	ENST00000416219.7 link	c.41G>C	p.Gly14Ala	missense_variant	Exon 1 of 28	1		ENSP00000397925.2		O75185-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000590

AC:

AN:

169494

AF XY:

0.0000105

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000143

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000425

AC:

AN:

1412538

Hom.:

Cov.:

AF XY:

0.00000428

AC XY:

AN XY:

700638

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29986

American (AMR)

AF:

0.00

AC:

AN:

38690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25058

East Asian (EAS)

AF:

0.00

AC:

AN:

34994

South Asian (SAS)

AF:

0.00

AC:

AN:

82112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5550

European-Non Finnish (NFE)

AF:

0.00000551

AC:

AN:

1088854

Other (OTH)

AF:

0.00

AC:

AN:

58244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Benign

4.5

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.0047

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00084

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.038

T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

-0.34

N;N

PhyloP100

0.81

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.040

N;N

REVEL

Benign

0.25

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.13

MutPred

0.30

Loss of ubiquitination at K11 (P = 0.0631);Loss of ubiquitination at K11 (P = 0.0631);

MVP

0.16

ClinPred

0.045

GERP RS

-0.97

PromoterAI

0.045

Neutral

(source)

Varity_R

0.15

gMVP

0.27

Mutation Taster

=95/5

polymorphism

(source)

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

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NM_014861.4:c.41G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over