12-9995251-T-C

Variant names:

• chr12-9995251-T-C
• rs521040
• NM_016509.4:c.439-5A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016509.4(CLEC1B):​c.439-5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,606,662 control chromosomes in the GnomAD database, including 60,491 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (7140 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53351 hom.)
• Consequence: CLEC1B NM_016509.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005377
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.610
• Publications: 28 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016509.4. 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
	CLEC1B	NM_016509.4	MANE Select	c.439-5A>G		splice_region intron	N/A	NP_057593.3	Q9P126-1
	CLEC1B	NM_001393342.1		c.439-5A>G		splice_region intron	N/A	NP_001380271.1	Q9P126-1
	CLEC1B	NM_001099431.2		c.340-5A>G		splice_region intron	N/A	NP_001092901.1	Q9P126-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLEC1B	ENST00000298527.11	TSL:1 MANE Select	c.439-5A>G		splice_region intron	N/A	ENSP00000298527.6	Q9P126-1
	CLEC1B	ENST00000348658.4	TSL:1	c.340-5A>G		splice_region intron	N/A	ENSP00000327169.6	Q9P126-2
	CLEC1B	ENST00000428126.6	TSL:1	c.340-5A>G		splice_region intron	N/A	ENSP00000406338.2	Q9P126-2

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45153 AN: 151914 Hom.: 7120 Cov.: 32

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.298

GnomAD2 exomes AF: 0.276 AC: 68702 AN: 248558 AF XY: 0.287

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.242

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.265

Gnomad OTH exome AF: 0.285

GnomAD4 exome AF: 0.266 AC: 386887 AN: 1454628 Hom.: 53351 Cov.: 28 AF XY: 0.271 AC XY: 196399 AN XY: 724050

African (AFR) AF: 0.394 AC: 13132 AN: 33292

American (AMR) AF: 0.175 AC: 7810 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 8592 AN: 26018

East Asian (EAS) AF: 0.211 AC: 8361 AN: 39614

South Asian (SAS) AF: 0.401 AC: 34571 AN: 86134

European-Finnish (FIN) AF: 0.237 AC: 12608 AN: 53140

Middle Eastern (MID) AF: 0.379 AC: 2176 AN: 5748

European-Non Finnish (NFE) AF: 0.256 AC: 282699 AN: 1105900

Other (OTH) AF: 0.282 AC: 16938 AN: 60100

GnomAD4 genome AF: 0.297 AC: 45217 AN: 152034 Hom.: 7140 Cov.: 32 AF XY: 0.298 AC XY: 22138 AN XY: 74306

African (AFR) AF: 0.398 AC: 16508 AN: 41458

American (AMR) AF: 0.229 AC: 3501 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1097 AN: 3466

East Asian (EAS) AF: 0.235 AC: 1219 AN: 5182

South Asian (SAS) AF: 0.421 AC: 2026 AN: 4814

European-Finnish (FIN) AF: 0.231 AC: 2444 AN: 10578

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17467 AN: 67960

Other (OTH) AF: 0.301 AC: 635 AN: 2108

Alfa AF: 0.274 Hom.: 26125

Bravo AF: 0.298

Asia WGS AF: 0.347 AC: 1207 AN: 3478

EpiCase AF: 0.270

EpiControl AF: 0.283

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.5
DANN	Benign	0.66
PhyloP100		0.61
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00054
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.020		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: rs521040; hg19: chr12-10147850; COSMIC: COSV53725626;