chrX-150769077-T-A

Variant names:

• chrX-150769077-T-A
• rs375281355
• NM_031462.4:c.746A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_031462.4(CD99L2):​c.746A>T​(p.Gln249Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,164,425 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 38 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.00013 (0 hom. 38 hem.)
• Consequence: CD99L2 NM_031462.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56
• Publications: 2 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.2582685).
• BS2: High Hemizygotes in GnomAdExome4 at 38 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD99L2	NM_031462.4	c.746A>T	p.Gln249Leu	missense_variant	Exon 11 of 11	ENST00000370377.8	NP_113650.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD99L2	ENST00000370377.8	c.746A>T	p.Gln249Leu	missense_variant	Exon 11 of 11	1	NM_031462.4	ENSP00000359403.3

Frequencies

GnomAD3 genomes AF: 0.0000798 AC: 9 AN: 112737 Hom.: 0 Cov.: 24

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: 0.000169

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000363 AC: 5 AN: 137617 AF XY: 0.0000220

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: 0.0000753

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 132 AN: 1051688 Hom.: 0 Cov.: 31 AF XY: 0.000111 AC XY: 38 AN XY: 342602

African (AFR) AF: 0.00 AC: 0 AN: 22894

American (AMR) AF: 0.00 AC: 0 AN: 23951

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17844

East Asian (EAS) AF: 0.00 AC: 0 AN: 26799

South Asian (SAS) AF: 0.00 AC: 0 AN: 47076

European-Finnish (FIN) AF: 0.0000253 AC: 1 AN: 39563

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3963

European-Non Finnish (NFE) AF: 0.000156 AC: 129 AN: 825407

Other (OTH) AF: 0.0000453 AC: 2 AN: 44191

GnomAD4 genome AF: 0.0000798 AC: 9 AN: 112737 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34897

African (AFR) AF: 0.00 AC: 0 AN: 31027

American (AMR) AF: 0.00 AC: 0 AN: 10727

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3575

South Asian (SAS) AF: 0.00 AC: 0 AN: 2766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6247

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000169 AC: 9 AN: 53299

Other (OTH) AF: 0.00 AC: 0 AN: 1525

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.776A>T (p.Q259L) alteration is located in exon 12 (coding exon 12) of the CD99L2 gene. This alteration results from a A to T substitution at nucleotide position 776, causing the glutamine (Q) at amino acid position 259 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	0.16
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;.;.;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.60	T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;.;.;.
PhyloP100		2.6
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.7	D;.;D;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.011	D;.;D;D;D
Sift4G	Uncertain	0.043	D;T;D;D;T
Polyphen		0.99	D;.;.;D;D
Vest4		0.46
MVP		0.34
MPC		0.22
ClinPred		0.62	D
GERP RS		3.2
Varity_R		0.19
gMVP		0.27
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs375281355; hg19: chrX-149937550;