12-9979515-A-G

Position:

• chr12-9979515-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138337.6(CLEC12A):​c.370A>G​(p.Lys124Glu) 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 benign outcome for this variant. 15/21 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)
• Consequence: CLEC12A NM_138337.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.644

Genes affected

CLEC12A (HGNC:31713): (C-type lectin domain family 12 member A) This gene encodes a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. Members of this family share a common protein fold and have diverse functions, such as cell adhesion, cell-cell signaling, glycoprotein turnover, and roles in inflammation and immune response. The protein encoded by this gene is a negative regulator of granulocyte and monocyte function. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. This gene is closely linked to other CTL/CTLD superfamily members in the natural killer gene complex region on chromosome 12p13. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06049326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLEC12A	NM_138337.6	c.370A>G	p.Lys124Glu	missense_variant	3/6	ENST00000304361.9	NP_612210.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLEC12A	ENST00000304361.9	c.370A>G	p.Lys124Glu	missense_variant	3/6	1	NM_138337.6	ENSP00000302804	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2024

The c.400A>G (p.K134E) alteration is located in exon 4 (coding exon 4) of the CLEC12A gene. This alteration results from a A to G substitution at nucleotide position 400, causing the lysine (K) at amino acid position 134 to be replaced by a glutamic acid (E). 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	Benign	0.094
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.8
DANN	Benign	0.46
DEOGEN2	Benign	0.039	.;.;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.52	T;T;T;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.060	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	.;.;L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Benign	0.024
Sift	Benign	0.21	T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.010	B;.;B;.;B
Vest4		0.15
MutPred		0.45		.;Gain of catalytic residue at K129 (P = 0.0055);Gain of catalytic residue at K129 (P = 0.0055);Gain of catalytic residue at K129 (P = 0.0055);.;
MVP		0.030
MPC		0.017
ClinPred		0.044	T
GERP RS		0.82
Varity_R		0.078
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-10132114;