chr12-9980699-C-A

Position:

• chr12-9980699-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_138337.6(CLEC12A):​c.497C>A​(p.Ala166Asp) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A166V) has been classified 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: 2.09

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLEC12A	NM_138337.6	c.497C>A	p.Ala166Asp	missense_variant	4/6	ENST00000304361.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLEC12A	ENST00000304361.9	c.497C>A	p.Ala166Asp	missense_variant	4/6	1	NM_138337.6	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jan 24, 2024

The c.527C>A (p.A176D) alteration is located in exon 5 (coding exon 5) of the CLEC12A gene. This alteration results from a C to A substitution at nucleotide position 527, causing the alanine (A) at amino acid position 176 to be replaced by an aspartic acid (D). 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	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	0.86	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.84
MutPred		0.73		.;Gain of catalytic residue at N165 (P = 0.025);Gain of catalytic residue at N165 (P = 0.025);.;
MVP		0.23
MPC		0.12
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.85

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: chr12-10133298; COSMIC: COSV58560607; COSMIC: COSV58560607;