Genetic Variant CLEC2D:p.Ser57Arg (chr12-9681032-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013269.6(CLEC2D):c.171C>A(p.Ser57Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000757 in 1,321,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

CLEC2D
NM_013269.6 missense, splice_region

Scores

Splicing: ADA: 0.00003056

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.588

Publications

0 publications found

Variant links:

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]

CLEC2D links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11700669).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013269.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLEC2D	NM_013269.6	MANE Select	c.171C>A	p.Ser57Arg	missense splice_region	Exon 2 of 5	NP_037401.1	Q9UHP7-1
CLEC2D	NM_001004419.5		c.171C>A	p.Ser57Arg	missense splice_region	Exon 2 of 6	NP_001004419.1	Q9UHP7-3
CLEC2D	NM_001197318.3		c.171C>A	p.Ser57Arg	missense splice_region	Exon 2 of 4	NP_001184247.1	Q9UHP7-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLEC2D	ENST00000290855.11	TSL:1 MANE Select	c.171C>A	p.Ser57Arg	missense splice_region	Exon 2 of 5	ENSP00000290855.6	Q9UHP7-1
CLEC2D	ENST00000261340.11	TSL:1	c.171C>A	p.Ser57Arg	missense splice_region	Exon 2 of 6	ENSP00000261340.7	Q9UHP7-3
CLEC2D	ENST00000430909.5	TSL:1	c.108C>A	p.Ser36Arg	missense splice_region	Exon 1 of 5	ENSP00000413045.1	A0A0C4DG81

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.57e-7

AC:

AN:

1321774

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

664610

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30502

American (AMR)

AF:

0.00

AC:

AN:

44118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25102

East Asian (EAS)

AF:

0.00

AC:

AN:

38982

South Asian (SAS)

AF:

0.00

AC:

AN:

82754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5498

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

987328

Other (OTH)

AF:

0.00

AC:

AN:

55638

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.035

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0097

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.63

M_CAP

Benign

0.0017

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

-0.59

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.12

Sift

Benign

0.34

Sift4G

Benign

0.43

Polyphen

1.0

Vest4

0.19

MutPred

0.59

Gain of catalytic residue at M52 (P = 0)

MVP

0.068

MPC

0.11

ClinPred

0.61

GERP RS

-2.4

PromoterAI

0.00040

Neutral

(source)

Varity_R

0.044

gMVP

0.29

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000031

dbscSNV1_RF

Benign

0.16

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over