Genetic Variant NM_031462.4:c.290A>G (chrX-150795474-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_031462.4(CD99L2):c.290A>G(p.His97Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,208,773 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000038 ( 0 hom. 17 hem. )

Consequence

CD99L2
NM_031462.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.726

Publications

0 publications found

Variant links:

Genes affected

CD99L2 (HGNC:18237): (CD99 molecule like 2) This gene encodes a cell-surface protein that is similar to CD99. A similar protein in mouse functions as an adhesion molecule during leukocyte extravasation. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

CD99L2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.088460684).

BS2

High Hemizygotes in GnomAdExome4 at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD99L2	NM_031462.4 link	c.290A>G	p.His97Arg	missense_variant	Exon 5 of 11	ENST00000370377.8	NP_113650.2	Q8TCZ2-1A0A024RC16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD99L2	ENST00000370377.8 link	c.290A>G	p.His97Arg	missense_variant	Exon 5 of 11	1	NM_031462.4	ENSP00000359403.3		Q8TCZ2-1

Frequencies

GnomAD3 genomes

AF:

0.0000271

AC:

AN:

110789

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000567

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000327

AC:

AN:

183264

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1097984

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

363356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26392

American (AMR)

AF:

0.0000853

AC:

AN:

35186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19377

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54131

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.0000451

AC:

AN:

841945

Other (OTH)

AF:

0.0000217

AC:

AN:

46087

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000271

AC:

AN:

110789

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33017

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30418

American (AMR)

AF:

0.00

AC:

AN:

10377

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3543

South Asian (SAS)

AF:

0.00

AC:

AN:

2554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5899

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

52949

Other (OTH)

AF:

0.00

AC:

AN:

1485

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000174

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.302A>G (p.H101R) alteration is located in exon 5 (coding exon 5) of the CD99L2 gene. This alteration results from a A to G substitution at nucleotide position 302, causing the histidine (H) at amino acid position 101 to be replaced by an arginine (R). 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

0.061

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.022

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.13

T;.;.

FATHMM_MKL

Benign

0.0058

LIST_S2

Benign

0.51

T;T;T

M_CAP

Benign

0.0027

MetaRNN

Benign

0.088

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.65

N;.;.

PhyloP100

-0.73

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.8

D;.;D

REVEL

Benign

0.024

Sift

Benign

0.59

T;.;T

Sift4G

Benign

0.90

T;T;T

Polyphen

0.0050

B;.;B

Vest4

0.030

MVP

0.55

MPC

0.088

ClinPred

0.036

GERP RS

-4.8

Varity_R

0.098

gMVP

0.046

Mutation Taster

=99/1

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_031462.4:c.290A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over