12-10126643-C-T

Variant names:

• chr12-10126643-C-T
• rs762084926
• NM_197947.3:c.268G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_197947.3(CLEC7A):​c.268G>A​(p.Glu90Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000014 (0 hom.)
• Consequence: CLEC7A NM_197947.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.213
• Publications: 0 publications found

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

ENSG00000299754 (HGNC:):

ACMG classification

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=0.08269721).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_197947.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLEC7A	NM_197947.3	MANE Select	c.268G>A	p.Glu90Lys	missense	Exon 3 of 6	NP_922938.1	Q9BXN2-1
	CLEC7A	NM_197948.3		c.268G>A	p.Glu90Lys	missense	Exon 3 of 5	NP_922939.1	Q9BXN2-3
	CLEC7A	NM_022570.5		c.202+1104G>A		intron	N/A	NP_072092.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLEC7A	ENST00000304084.13	TSL:1 MANE Select	c.268G>A	p.Glu90Lys	missense	Exon 3 of 6	ENSP00000302569.8	Q9BXN2-1
	CLEC7A	ENST00000533022.5	TSL:1	c.268G>A	p.Glu90Lys	missense	Exon 3 of 5	ENSP00000431461.1	Q9BXN2-3
	CLEC7A	ENST00000353231.9	TSL:1	c.202+1104G>A		intron	N/A	ENSP00000266456.6	Q9BXN2-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248412 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460650 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726644

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

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111532

Other (OTH) AF: 0.00 AC: 0 AN: 60332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.21
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.040
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.32	T
Polyphen		0.068	B
Vest4		0.29
MutPred		0.39		Gain of ubiquitination at E90 (P = 0.0114)
MVP		0.25
MPC		0.045
ClinPred		0.95	D
GERP RS		1.1
Varity_R		0.14
gMVP		0.63
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs762084926; hg19: chr12-10279242;