12-10015363-A-C

Position:

• chr12-10015363-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000338896.11(CLEC12B):​c.521A>C​(p.Asp174Ala) 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. 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)
• Consequence: CLEC12B ENST00000338896.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

Genes affected

CLEC12B (HGNC:31966): (C-type lectin domain family 12 member B) Enables protein phosphatase binding activity and signaling receptor inhibitor activity. Involved in natural killer cell inhibitory signaling pathway; negative regulation of natural killer cell mediated cytotoxicity; and negative regulation of signaling receptor activity. Located in external side of plasma membrane. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10051224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLEC12B	NM_001129998.3	c.521A>C	p.Asp174Ala	missense_variant	4/6	ENST00000338896.11	NP_001123470.1
LOC102724020	NR_169587.1	n.744T>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLEC12B	ENST00000338896.11	c.521A>C	p.Asp174Ala	missense_variant	4/6	1	NM_001129998.3	ENSP00000344563	P1
	ENST00000544225.1	n.659T>G		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jul 06, 2021

The c.521A>C (p.D174A) alteration is located in exon 4 (coding exon 4) of the CLEC12B gene. This alteration results from a A to C substitution at nucleotide position 521, causing the aspartic acid (D) at amino acid position 174 to be replaced by an alanine (A). 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	0.084
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0060	.;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.14	T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.68	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.063
Sift	Benign	0.65	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.57	P;P
Vest4		0.29
MutPred		0.43		Loss of ubiquitination at K170 (P = 0.0334);Loss of ubiquitination at K170 (P = 0.0334);
MVP		0.21
MPC		0.16
ClinPred		0.22	T
GERP RS		3.4
Varity_R		0.12
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1865457691; hg19: chr12-10167962;