7-139483321-C-T

Variant summary

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

The NM_198508.4(KLRG2):c.322G>A(p.Glu108Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000358 in 1,396,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: KLRG2 NM_198508.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.247

Genes affected

KLRG2 (HGNC:24778): (killer cell lectin like receptor G2) Predicted to enable carbohydrate binding activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.084962904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLRG2	NM_198508.4	c.322G>A	p.Glu108Lys	missense_variant	1/5	ENST00000340940.5
KLRG2	XM_011516140.3	c.322G>A	p.Glu108Lys	missense_variant	1/4
KLRG2	XM_011516141.3	c.322G>A	p.Glu108Lys	missense_variant	1/4
KLRG2	XM_005250311.4	c.322G>A	p.Glu108Lys	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLRG2	ENST00000340940.5	c.322G>A	p.Glu108Lys	missense_variant	1/5	1	NM_198508.4	P1
KLRG2	ENST00000393039.2	c.322G>A	p.Glu108Lys	missense_variant	1/2	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000404 AC: 6 AN: 148504 Hom.: 0 AF XY: 0.0000239 AC XY: 2 AN XY: 83836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000381

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000785

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000358 AC: 50 AN: 1396290 Hom.: 0 Cov.: 34 AF XY: 0.0000390 AC XY: 27 AN XY: 692260

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000264

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: 0.0000431

Gnomad4 OTH exome AF: 0.0000344

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000371 AC: 4

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

Feb 10, 2022

The c.322G>A (p.E108K) alteration is located in exon 1 (coding exon 1) of the KLRG2 gene. This alteration results from a G to A substitution at nucleotide position 322, causing the glutamic acid (E) at amino acid position 108 to be replaced by a lysine (K). 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	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0056	T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.085	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.052
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.41	T;T
Polyphen		0.61	P;P
Vest4		0.077
MutPred		0.18		Gain of ubiquitination at E108 (P = 0.006);Gain of ubiquitination at E108 (P = 0.006);
MVP		0.41
MPC		1.1
ClinPred		0.13	T
GERP RS		2.5
Varity_R		0.16
gMVP		0.29

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: rs772088472; hg19: chr7-139168067;