Genetic Variant CLEC7A:p.Ile223Thr (chr12-10118534-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_197947.3(CLEC7A):c.668T>C(p.Ile223Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,580 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I223S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CLEC7A
NM_197947.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.48

Publications

0 publications found

Variant links:

Genes affected

CLEC7A (HGNC:14558): (C-type lectin domain containing 7A) This gene encodes a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. The encoded glycoprotein is a small type II membrane receptor with an extracellular C-type lectin-like domain fold and a cytoplasmic domain with an immunoreceptor tyrosine-based activation motif. It functions as a pattern-recognition receptor that recognizes a variety of beta-1,3-linked and beta-1,6-linked glucans from fungi and plants, and in this way plays a role in innate immune response. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. 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]

CLEC7A Gene-Disease associations (from GenCC):

chronic mucocutaneous candidiasis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CLEC7A links:

ENSG00000299754 (HGNC:):

ENSG00000299754 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLEC7A	NM_197947.3 link	c.668T>C	p.Ile223Thr	missense_variant	Exon 6 of 6	ENST00000304084.13	NP_922938.1	Q9BXN2-1Q68D78A0A024RAN9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLEC7A	ENST00000304084.13 link	c.668T>C	p.Ile223Thr	missense_variant	Exon 6 of 6	1	NM_197947.3	ENSP00000302569.8		Q9BXN2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460580

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726708

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1110868

Other (OTH)

AF:

0.00

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

.;.;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Benign

-0.99

PhyloP100

3.5

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Benign

0.18

Sift

Uncertain

0.0060

D;D;D

Sift4G

Benign

0.14

T;D;D

Polyphen

1.0

D;D;D

Vest4

0.71

MutPred

0.40

.;.;Loss of stability (P = 0.0034);

MVP

0.44

MPC

0.24

ClinPred

0.93

GERP RS

3.8

Varity_R

0.54

gMVP

0.65

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over