12-9922199-C-A

Variant names:

• chr12-9922199-C-A
• rs1048227270
• NM_001130711.2:c.173G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001130711.2(CLEC2A):​c.173G>T​(p.Cys58Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. C58S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLEC2A NM_001130711.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.20
• Publications: 0 publications found

Genes affected

CLEC2A (HGNC:24191): (C-type lectin domain family 2 member A) Enables protein homodimerization activity. Predicted to be involved in natural killer cell mediated cytotoxicity. Predicted to act upstream of or within several processes, including T cell receptor signaling pathway; regulation of actin filament polymerization; and regulation of interleukin-2 production. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130711.2. 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
	CLEC2A	NM_001130711.2	MANE Select	c.173G>T	p.Cys58Phe	missense	Exon 3 of 5	NP_001124183.1	Q6UVW9-1
	CLEC2A	NM_207375.3		c.173G>T	p.Cys58Phe	missense	Exon 3 of 5	NP_997258.1	Q6UVW9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLEC2A	ENST00000455827.2	TSL:1 MANE Select	c.173G>T	p.Cys58Phe	missense	Exon 3 of 5	ENSP00000396163.1	Q6UVW9-1
	CLEC2A	ENST00000339766.8	TSL:1	c.173G>T	p.Cys58Phe	missense	Exon 3 of 5	ENSP00000339732.4	Q6UVW9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0060	T
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.2
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-10	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.78		Gain of catalytic residue at A57 (P = 5e-04)
MVP		0.26
ClinPred		1.0	D
GERP RS		2.6
Varity_R		0.93
gMVP		0.72
Mutation Taster		=83/17	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: rs1048227270; hg19: chr12-10074798;