Genetic Variant NM_031462.4:c.682G>A (chrX-150770343-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_031462.4(CD99L2):c.682G>A(p.Gly228Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,210,496 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000016 ( 0 hom. 6 hem. )

Consequence

CD99L2
NM_031462.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.66

Publications

5 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3055788).

BS2

High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD99L2	NM_031462.4 link	c.682G>A	p.Gly228Arg	missense_variant	Exon 10 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.682G>A	p.Gly228Arg	missense_variant	Exon 10 of 11	1	NM_031462.4	ENSP00000359403.3		Q8TCZ2-1

Frequencies

GnomAD3 genomes

AF:

0.00000889

AC:

AN:

112483

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183368

AF XY:

0.0000147

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:

0.0000122

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1098013

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363377

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.00

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.00

AC:

AN:

54133

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40507

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.0000202

AC:

AN:

841957

Other (OTH)

AF:

0.0000217

AC:

AN:

46093

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000889

AC:

AN:

112483

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34629

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30933

American (AMR)

AF:

0.00

AC:

AN:

10711

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3582

South Asian (SAS)

AF:

0.00

AC:

AN:

2705

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53285

Other (OTH)

AF:

0.00

AC:

AN:

1511

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 23, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.712G>A (p.G238R) alteration is located in exon 11 (coding exon 11) of the CD99L2 gene. This alteration results from a G to A substitution at nucleotide position 712, causing the glycine (G) at amino acid position 238 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

Pathogenic

0.65

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.;.;.;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

T;T;T;T;T

M_CAP

Benign

0.077

MetaRNN

Benign

0.31

T;T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Pathogenic

3.1

M;.;.;.;.

PhyloP100

3.7

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-4.0

D;.;D;D;D

REVEL

Benign

0.16

Sift

Benign

0.042

D;.;D;D;D

Sift4G

Benign

0.078

T;T;D;D;T

Polyphen

0.78

P;.;.;D;D

Vest4

0.48

MutPred

0.28

Loss of sheet (P = 0.0315);.;.;.;.;

MVP

0.39

MPC

0.26

ClinPred

0.98

GERP RS

4.2

Varity_R

0.31

gMVP

0.61

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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.682G>A

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