chr19-54742110-G-C

Position:

• chr19-54742110-G-C

Variant summary

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

The ENST00000342376.4(KIR2DL3):​c.201G>C​(p.Lys67Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000316 in 1,613,238 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: KIR2DL3 ENST00000342376.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.01

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=0.018308312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR2DL3	NM_015868.3	c.201G>C	p.Lys67Asn	missense_variant	3/8	ENST00000342376.4	NP_056952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIR2DL3	ENST00000342376.4	c.201G>C	p.Lys67Asn	missense_variant	3/8	1	NM_015868.3	ENSP00000342215	P1

Frequencies

GnomAD3 genomes AF: 0.000258 AC: 39 AN: 151376 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000384

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.000343 AC: 78 AN: 227412 Hom.: 15 AF XY: 0.000311 AC XY: 38 AN XY: 122170

Gnomad AFR exome AF: 0.000344

Gnomad AMR exome AF: 0.000125

Gnomad ASJ exome AF: 0.000115

Gnomad EAS exome AF: 0.000666

Gnomad SAS exome AF: 0.000401

Gnomad FIN exome AF: 0.000442

Gnomad NFE exome AF: 0.000358

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000322 AC: 471 AN: 1461742 Hom.: 1 Cov.: 58 AF XY: 0.000327 AC XY: 238 AN XY: 727174

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.000338

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000257 AC: 39 AN: 151496 Hom.: 0 Cov.: 31 AF XY: 0.000216 AC XY: 16 AN XY: 74072

Gnomad4 AFR AF: 0.000194

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000384

Gnomad4 OTH AF: 0.000477

ESP6500AA AF: 0.000247 AC: 1

ESP6500EA AF: 0.000501 AC: 4

ExAC AF: 0.000353 AC: 40

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 17, 2022

The c.201G>C (p.K67N) alteration is located in exon 3 (coding exon 3) of the KIR2DL3 gene. This alteration results from a G to C substitution at nucleotide position 201, causing the lysine (K) at amino acid position 67 to be replaced by an asparagine (N). 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	0.098
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.22
DANN	Benign	0.41
DEOGEN2	Benign	0.014	T
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0018	N
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.085	N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.019
Sift	Benign	0.85	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.096
MutPred		0.27		Loss of ubiquitination at K67 (P = 0.0167);
MVP		0.10
MPC		1.9
ClinPred		0.0029	T
GERP RS		-3.2
Varity_R		0.10
gMVP		0.058

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: rs145638569; hg19: chr19-55253556;