chr12-9893436-T-C

Position:

• chr12-9893436-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001190765.1(KLRF2):​c.374T>C​(p.Ile125Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000392 in 1,276,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000039 (0 hom.)
• Consequence: KLRF2 NM_001190765.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.462

Genes affected

KLRF2 (HGNC:37646): (killer cell lectin like receptor F2) Enables protein homodimerization activity. Predicted to be involved in natural killer cell degranulation and positive regulation of cytokine production. Predicted to act upstream of or within natural killer cell activation and positive regulation of natural killer cell mediated cytotoxicity. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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]

CLEC2A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3597948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLRF2	NM_001190765.1	c.374T>C	p.Ile125Thr	missense_variant	5/6	ENST00000535540.1	NP_001177694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLRF2	ENST00000535540.1	c.374T>C	p.Ile125Thr	missense_variant	5/6	1	NM_001190765.1	ENSP00000438244.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000392 AC: 5 AN: 1276000 Hom.: 0 Cov.: 20 AF XY: 0.00000315 AC XY: 2 AN XY: 634470

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: 0.00000508

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jun 04, 2024

The c.374T>C (p.I125T) alteration is located in exon 5 (coding exon 5) of the KLRF2 gene. This alteration results from a T to C substitution at nucleotide position 374, causing the isoleucine (I) at amino acid position 125 to be replaced by a threonine (T). 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	0.61
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.039
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Vest4		0.41
MutPred		0.75		Gain of disorder (P = 0.011);
MVP		0.061
ClinPred		0.33	T
GERP RS		0.97
Varity_R		0.57
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-10046035;