12-9688033-T-C

Variant names:

• chr12-9688033-T-C
• rs1865787137
• NM_013269.6:c.304T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013269.6(CLEC2D):​c.304T>C​(p.Phe102Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,108 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: 6.8e-7 (0 hom.)
• Consequence: CLEC2D NM_013269.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.128

Genes affected

CLEC2D (HGNC:14351): (C-type lectin domain family 2 member D) This gene encodes a member of the natural killer cell receptor C-type lectin family. The encoded protein inhibits osteoclast formation and contains a transmembrane domain near the N-terminus as well as the C-type lectin-like extracellular domain. Several alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3078097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLEC2D	NM_013269.6	c.304T>C	p.Phe102Leu	missense_variant	Exon 3 of 5	ENST00000290855.11	NP_037401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLEC2D	ENST00000290855.11	c.304T>C	p.Phe102Leu	missense_variant	Exon 3 of 5	1	NM_013269.6	ENSP00000290855.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460108 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726380

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.304T>C (p.F102L) alteration is located in exon 3 (coding exon 3) of the CLEC2D gene. This alteration results from a T to C substitution at nucleotide position 304, causing the phenylalanine (F) at amino acid position 102 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	Pathogenic	0.97
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.030	.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.63	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.8	M;M;.;M;.;.;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D;D;D
REVEL	Benign	0.21
Sift	Benign	0.12	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.078	T;D;D;D;T;T;D;T;T
Polyphen		0.85	P;P;.;P;.;.;.;.;.
Vest4		0.35
MutPred		0.51		Gain of catalytic residue at R101 (P = 0.0044);Gain of catalytic residue at R101 (P = 0.0044);.;Gain of catalytic residue at R101 (P = 0.0044);.;.;.;.;.;
MVP		0.15
MPC		0.24
ClinPred		0.69	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.62
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs1865787137; hg19: chr12-9840629;