chrX-136648308-C-G

Position:

• chrX-136648308-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000074.3(CD40LG):​c.60C>G​(p.Ser20Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CD40LG NM_000074.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0820

Genes affected

CD40LG (HGNC:11935): (CD40 ligand) The protein encoded by this gene is expressed on the surface of T cells. It regulates B cell function by engaging CD40 on the B cell surface. A defect in this gene results in an inability to undergo immunoglobulin class switch and is associated with hyper-IgM syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain CD40 ligand, membrane form (size 260) in uniprot entity CD40L_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000074.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08376846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD40LG	NM_000074.3	c.60C>G	p.Ser20Arg	missense_variant	1/5	ENST00000370629.7	NP_000065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD40LG	ENST00000370629.7	c.60C>G	p.Ser20Arg	missense_variant	1/5	1	NM_000074.3	ENSP00000359663	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyper-IgM syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 08, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CD40LG protein function. ClinVar contains an entry for this variant (Variation ID: 2083129). This variant has not been reported in the literature in individuals affected with CD40LG-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 20 of the CD40LG protein (p.Ser20Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Uncertain	0.51	D;T
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.084	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.11
Sift	Benign	0.076	T;T
Sift4G	Uncertain	0.058	T;T
Polyphen		0.0010	B;B
Vest4		0.16
MutPred		0.47		Loss of ubiquitination at K22 (P = 0.045);Loss of ubiquitination at K22 (P = 0.045);
MVP		0.48
MPC		0.49
ClinPred		0.12	T
GERP RS		-2.2
Varity_R		0.17
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: chrX-135730467;