Genetic Variant NM_001008489.4:c.711T>G (chr2-169701682-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001008489.4(PHOSPHO2):c.711T>G(p.Phe237Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

PHOSPHO2
NM_001008489.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.618

Variant links:

Genes affected

PHOSPHO2 (HGNC:28316): (phosphatase, orphan 2) Predicted to enable phosphatase activity. Predicted to be involved in dephosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

PHOSPHO2 links:

PHOSPHO2-KLHL23 (HGNC:):

PHOSPHO2-KLHL23 links:

KLHL23 (HGNC:27506): (kelch like family member 23)

KLHL23 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060285687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOSPHO2	NM_001008489.4 link	c.711T>G	p.Phe237Leu	missense_variant	Exon 4 of 4	ENST00000359744.8	NP_001008489.1	Q8TCD6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOSPHO2	ENST00000359744.8 link	c.711T>G	p.Phe237Leu	missense_variant	Exon 4 of 4	1	NM_001008489.4	ENSP00000352782.3		Q8TCD6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1394248

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693030

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.26e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.711T>G (p.F237L) alteration is located in exon 4 (coding exon 1) of the PHOSPHO2 gene. This alteration results from a T to G substitution at nucleotide position 711, causing the phenylalanine (F) at amino acid position 237 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0072

T;T;T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.43

.;.;T;.

M_CAP

Benign

0.0036

MetaRNN

Benign

0.060

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.47

N;N;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

0.87

.;.;.;N

REVEL

Benign

0.043

Sift

Benign

0.31

.;.;.;T

Sift4G

Benign

0.39

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.13

MutPred

0.46

Loss of ubiquitination at K240 (P = 0.1264);Loss of ubiquitination at K240 (P = 0.1264);Loss of ubiquitination at K240 (P = 0.1264);Loss of ubiquitination at K240 (P = 0.1264);

MVP

0.030

MPC

0.10

ClinPred

0.23

GERP RS

2.6

Varity_R

0.030

gMVP

0.17

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over