12-8539944-C-G

Variant names:

• chr12-8539944-C-G
• NM_014358.4:c.41G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014358.4(CLEC4E):​c.41G>C​(p.Arg14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 1,439,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000042 (0 hom.)
• Consequence: CLEC4E NM_014358.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.313

Genes affected

CLEC4E (HGNC:14555): (C-type lectin domain family 4 member E) This gene encodes a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. Members of this family share a common protein fold and have diverse functions, such as cell adhesion, cell-cell signalling, glycoprotein turnover, and roles in inflammation and immune response. The encoded type II transmembrane protein is a downstream target of CCAAT/enhancer binding protein (C/EBP), beta (CEBPB) and may play a role in inflammation. Alternative splice variants have been described but their full-length sequence has not been determined. This gene is closely linked to other CTL/CTLD superfamily members on chromosome 12p13 in the natural killer gene complex region. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11666149).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLEC4E	NM_014358.4	c.41G>C	p.Arg14Thr	missense_variant	Exon 2 of 6	ENST00000299663.8	NP_055173.1
CLEC4E	NM_001410969.1	c.41G>C	p.Arg14Thr	missense_variant	Exon 2 of 5		NP_001397898.1
CLEC4E	XM_011520614.4	c.38-638G>C		intron_variant	Intron 1 of 4		XP_011518916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLEC4E	ENST00000299663.8	c.41G>C	p.Arg14Thr	missense_variant	Exon 2 of 6	1	NM_014358.4	ENSP00000299663.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000417 AC: 6 AN: 1439624 Hom.: 0 Cov.: 26 AF XY: 0.00000418 AC XY: 3 AN XY: 717610

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000550

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.41G>C (p.R14T) alteration is located in exon 2 (coding exon 2) of the CLEC4E gene. This alteration results from a G to C substitution at nucleotide position 41, causing the arginine (R) at amino acid position 14 to be replaced by a threonine (T). 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	0.082
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.8
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T;.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.67	T;.;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.5	N;D;N
REVEL	Benign	0.054
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.27	B;.;.
Vest4		0.25
MutPred		0.39		Loss of phosphorylation at T12 (P = 0.0683);Loss of phosphorylation at T12 (P = 0.0683);Loss of phosphorylation at T12 (P = 0.0683);
MVP		0.30
MPC		0.094
ClinPred		0.32	T
GERP RS		0.034
Varity_R		0.10
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: chr12-8692540;