7-139483378-C-T

Variant summary

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

The NM_198508.4(KLRG2):c.265G>A(p.Val89Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000361 in 1,384,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000036 (0 hom.)
• Consequence: KLRG2 NM_198508.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

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 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=0.036091417).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLRG2	NM_198508.4	c.265G>A	p.Val89Ile	missense_variant	1/5	ENST00000340940.5
KLRG2	XM_011516140.3	c.265G>A	p.Val89Ile	missense_variant	1/4
KLRG2	XM_011516141.3	c.265G>A	p.Val89Ile	missense_variant	1/4
KLRG2	XM_005250311.4	c.265G>A	p.Val89Ile	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLRG2	ENST00000340940.5	c.265G>A	p.Val89Ile	missense_variant	1/5	1	NM_198508.4	P1
KLRG2	ENST00000393039.2	c.265G>A	p.Val89Ile	missense_variant	1/2	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000723 AC: 1 AN: 138254 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 78928

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 SAS exome AF: 0.0000455

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000361 AC: 5 AN: 1384606 Hom.: 0 Cov.: 34 AF XY: 0.00000437 AC XY: 3 AN XY: 686308

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000292

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000276

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

Feb 28, 2023

The c.265G>A (p.V89I) 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 265, causing the valine (V) at amino acid position 89 to be replaced by an isoleucine (I). 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	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	20
Dann	Uncertain	0.97
DEOGEN2	Benign	0.0013	T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.41	T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.036	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.051
Sift	Uncertain	0.010	D;T
Sift4G	Uncertain	0.015	D;T
Polyphen		0.023	B;B
Vest4		0.045
MutPred		0.11		Loss of catalytic residue at V89 (P = 0.0416);Loss of catalytic residue at V89 (P = 0.0416);
MVP		0.092
MPC		0.66
ClinPred		0.17	T
GERP RS		2.4
Varity_R		0.093
gMVP		0.043

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: rs758932840; hg19: chr7-139168124;