19-54739521-C-A

Position:

• chr19-54739521-C-A

Variant summary

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

The ENST00000342376.4(KIR2DL3):​c.49C>A​(p.Gln17Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000803 in 1,613,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00085 (0 hom.)
• Consequence: KIR2DL3 ENST00000342376.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.507

Genes affected

KIR2DL3 (HGNC:6331): (killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3) Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer cells and subsets of T cells. The KIR genes are polymorphic and highly homologous and they are found in a cluster on chromosome 19q13.4 within the 1 Mb leukocyte receptor complex (LRC). The gene content of the KIR gene cluster varies among haplotypes, although several "framework" genes are found in all haplotypes (KIR3DL3, KIR3DP1, KIR3DL4, KIR3DL2). The KIR proteins are classified by the number of extracellular immunoglobulin domains (2D or 3D) and by whether they have a long (L) or short (S) cytoplasmic domain. KIR proteins with the long cytoplasmic domain transduce inhibitory signals upon ligand binding via an immune tyrosine-based inhibitory motif (ITIM), while KIR proteins with the short cytoplasmic domain lack the ITIM motif and instead associate with the TYRO protein tyrosine kinase binding protein to transduce activating signals. The ligands for several KIR proteins are subsets of HLA class I molecules; thus, KIR proteins are thought to play an important role in regulation of the immune response. [provided by RefSeq, Jul 2008]

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=0.019910514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR2DL3	NM_015868.3	c.49C>A	p.Gln17Lys	missense_variant	2/8	ENST00000342376.4	NP_056952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIR2DL3	ENST00000342376.4	c.49C>A	p.Gln17Lys	missense_variant	2/8	1	NM_015868.3	ENSP00000342215	P1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152162 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000965

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: 0.000735

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000678 AC: 112 AN: 165262 Hom.: 15 AF XY: 0.000791 AC XY: 70 AN XY: 88440

Gnomad AFR exome AF: 0.000345

Gnomad AMR exome AF: 0.0000478

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000706

Gnomad FIN exome AF: 0.0000610

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.000796

GnomAD4 exome AF: 0.000848 AC: 1240 AN: 1461496 Hom.: 0 Cov.: 71 AF XY: 0.000816 AC XY: 593 AN XY: 727060

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00108

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152162 Hom.: 0 Cov.: 35 AF XY: 0.000323 AC XY: 24 AN XY: 74328

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.000957

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000405 AC: 2

ExAC AF: 0.000731 AC: 78

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

May 16, 2023

The c.49C>A (p.Q17K) alteration is located in exon 2 (coding exon 2) of the KIR2DL3 gene. This alteration results from a C to A substitution at nucleotide position 49, causing the glutamine (Q) at amino acid position 17 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	0.14
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.9
DANN	Benign	0.82
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0031	N
M_CAP	Benign	0.00063	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N;N;N;N;N;N
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.061
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.23	T
Polyphen		0.075	B
Vest4		0.090
MVP		0.22
MPC		3.3
ClinPred		0.029	T
GERP RS		-0.84
Varity_R		0.077
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs371654293; hg19: chr19-55250967;