Genetic Variant ULBP2:p.Arg24Pro (chr6-149942143-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025217.4(ULBP2):c.71G>C(p.Arg24Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,858 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: 6.9e-7 ( 0 hom. )

Consequence

ULBP2
NM_025217.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.171

Publications

0 publications found

Variant links:

Genes affected

ULBP2 (HGNC:14894): (UL16 binding protein 2) This gene encodes a major histocompatibility complex (MHC) class I-related molecule that binds to the NKG2D receptor on natural killer (NK) cells to trigger release of multiple cytokines and chemokines that in turn contribute to the recruitment and activation of NK cells. The encoded protein undergoes further processing to generate the mature protein that is either anchored to membrane via a glycosylphosphatidylinositol moiety, or secreted. Many malignant cells secrete the encoded protein to evade immunosurveillance by NK cells. This gene is located in a cluster of multiple MHC class I-related genes on chromosome 6. [provided by RefSeq, Jul 2015]

ULBP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07272223).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ULBP2	NM_025217.4 link	c.71G>C	p.Arg24Pro	missense_variant	Exon 1 of 5	ENST00000367351.4	NP_079493.1	Q9BZM5
ULBP2	XM_047419377.1 link	c.71G>C	p.Arg24Pro	missense_variant	Exon 1 of 4		XP_047275333.1
ULBP2	XM_017011321.2 link	c.71G>C	p.Arg24Pro	missense_variant	Exon 1 of 4		XP_016866810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ULBP2	ENST00000367351.4 link	c.71G>C	p.Arg24Pro	missense_variant	Exon 1 of 5	1	NM_025217.4	ENSP00000356320.3		Q9BZM5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457858

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725170

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39512

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110930

Other (OTH)

AF:

0.00

AC:

AN:

60132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Aug 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.71G>C (p.R24P) alteration is located in exon 1 (coding exon 1) of the ULBP2 gene. This alteration results from a G to C substitution at nucleotide position 71, causing the arginine (R) at amino acid position 24 to be replaced by a proline (P). 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

0.092

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

7.0

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.0043

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.26

M_CAP

Benign

0.00098

MetaRNN

Benign

0.073

MetaSVM

Benign

-0.95

PhyloP100

-0.17

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.41

REVEL

Benign

0.044

Sift

Benign

0.15

Sift4G

Benign

0.31

Polyphen

0.0060

Vest4

0.14

MutPred

0.31

Loss of methylation at R24 (P = 0.0411);

MVP

0.21

MPC

0.0036

ClinPred

0.087

GERP RS

0.24

PromoterAI

0.022

Neutral

(source)

Varity_R

0.079

gMVP

0.12

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over