12-9926316-A-G

Variant names:

• chr12-9926316-A-G
• rs1014673032
• NM_001130711.2:c.83T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001130711.2(CLEC2A):​c.83T>C​(p.Ile28Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000323 in 1,549,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I28S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CLEC2A NM_001130711.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• Publications: 0 publications found

Genes affected

CLEC2A (HGNC:24191): (C-type lectin domain family 2 member A) Enables protein homodimerization activity. Predicted to be involved in natural killer cell mediated cytotoxicity. Predicted to act upstream of or within several processes, including T cell receptor signaling pathway; regulation of actin filament polymerization; and regulation of interleukin-2 production. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048734218).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130711.2. 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
	CLEC2A	NM_001130711.2	MANE Select	c.83T>C	p.Ile28Thr	missense	Exon 2 of 5	NP_001124183.1	Q6UVW9-1
	CLEC2A	NM_207375.3		c.83T>C	p.Ile28Thr	missense	Exon 2 of 5	NP_997258.1	Q6UVW9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLEC2A	ENST00000455827.2	TSL:1 MANE Select	c.83T>C	p.Ile28Thr	missense	Exon 2 of 5	ENSP00000396163.1	Q6UVW9-1
	CLEC2A	ENST00000339766.8	TSL:1	c.83T>C	p.Ile28Thr	missense	Exon 2 of 5	ENSP00000339732.4	Q6UVW9-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000633 AC: 1 AN: 158004 AF XY: 0.0000120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000165

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1397166 Hom.: 0 Cov.: 28 AF XY: 0.00000145 AC XY: 1 AN XY: 689268

African (AFR) AF: 0.00 AC: 0 AN: 31530

American (AMR) AF: 0.00 AC: 0 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25154

East Asian (EAS) AF: 0.00 AC: 0 AN: 35676

South Asian (SAS) AF: 0.00 AC: 0 AN: 79194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1077096

Other (OTH) AF: 0.00 AC: 0 AN: 57924

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74304

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000225 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.21
DANN	Benign	0.31
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0079	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.0080
Sift	Benign	0.31	T
Sift4G	Uncertain	0.033	D
Polyphen		0.48	P
Vest4		0.15
MutPred		0.46		Loss of stability (P = 0.0197)
MVP		0.10
ClinPred		0.045	T
GERP RS		0.67
Varity_R		0.032
gMVP		0.14
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1014673032; hg19: chr12-10078915;