12-9996859-T-C

Position:

• chr12-9996859-T-C

Variant summary

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

The NM_016509.4(CLEC1B):​c.425A>G​(p.Asn142Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CLEC1B NM_016509.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.803

Genes affected

CLEC1B (HGNC:24356): (C-type lectin domain family 1 member B) Natural killer (NK) cells express multiple calcium-dependent (C-type) lectin-like receptors, such as CD94 (KLRD1; MIM 602894) and NKG2D (KLRC4; MIM 602893), that interact with major histocompatibility complex class I molecules and either inhibit or activate cytotoxicity and cytokine secretion. CLEC2 is a C-type lectin-like receptor expressed in myeloid cells and NK cells (Colonna et al., 2000 [PubMed 10671229]).[supplied by OMIM, Jan 2011]

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=0.050623804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLEC1B	NM_016509.4	c.425A>G	p.Asn142Ser	missense_variant	4/6	ENST00000298527.11	NP_057593.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLEC1B	ENST00000298527.11	c.425A>G	p.Asn142Ser	missense_variant	4/6	1	NM_016509.4	ENSP00000298527.6
CLEC1B	ENST00000348658.4	c.326A>G	p.Asn109Ser	missense_variant	3/5	1		ENSP00000327169.6
CLEC1B	ENST00000428126.6	c.326A>G	p.Asn109Ser	missense_variant	5/7	1		ENSP00000406338.2
CLEC1B	ENST00000398937.6	c.146A>G	p.Asn49Ser	missense_variant	2/4	3		ENSP00000381910.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249462 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135348

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461750 Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.13
DANN	Benign	0.59
DEOGEN2	Benign	0.041	.;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.63	T;.;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.051	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.77	.;.;N;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.19	N;N;N;N
REVEL	Benign	0.024
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.84	T;T;T;T
Polyphen		0.0030, 0.0070	.;B;B;B
Vest4		0.11, 0.10, 0.11
MutPred		0.56		.;.;Gain of ubiquitination at K139 (P = 0.0817);.;
MVP		0.28
MPC		0.039
ClinPred		0.036	T
GERP RS		-2.1
Varity_R		0.10
gMVP		0.20

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

LitVar

Other links and lift over

dbSNP: rs769148753; hg19: chr12-10149458;