2-169701255-T-C

Position:

• chr2-169701255-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001008489.4(PHOSPHO2):​c.284T>C​(p.Ile95Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PHOSPHO2 NM_001008489.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.76

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-KLHL23 (HGNC:):

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

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHOSPHO2	NM_001008489.4	c.284T>C	p.Ile95Thr	missense_variant	4/4	ENST00000359744.8	NP_001008489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHOSPHO2	ENST00000359744.8	c.284T>C	p.Ile95Thr	missense_variant	4/4	1	NM_001008489.4	ENSP00000352782.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461470 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727012

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.284T>C (p.I95T) alteration is located in exon 4 (coding exon 1) of the PHOSPHO2 gene. This alteration results from a T to C substitution at nucleotide position 284, causing the isoleucine (I) at amino acid position 95 to be replaced by a threonine (T). 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	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	.;.;D;.;D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Pathogenic	3.2	M;M;M;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.6	.;.;.;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.89
MutPred		0.70		Loss of stability (P = 0.0136);Loss of stability (P = 0.0136);Loss of stability (P = 0.0136);Loss of stability (P = 0.0136);Loss of stability (P = 0.0136);
MVP		0.42
MPC		0.52
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.61
gMVP		0.80

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.

Other links and lift over

hg19: chr2-170557765;