19-54866553-C-T

Position:

• chr19-54866553-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006737.4(KIR3DL2):​c.1190C>T​(p.Thr397Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,613,670 control chromosomes in the GnomAD database, including 77,085 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (6010 hom., cov: 31)
  • Exomes 𝑓: 0.31 (71075 hom.)
• Consequence: KIR3DL2 NM_006737.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.309

Genes affected

KIR3DL2 (HGNC:6339): (killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 2) 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. This gene is one of the "framework" loci that is present on all haplotypes. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060640574).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR3DL2	NM_006737.4	c.1190C>T	p.Thr397Met	missense_variant	9/9	ENST00000326321.7	NP_006728.2
KIR3DL2	NM_001242867.2	c.1139C>T	p.Thr380Met	missense_variant	8/8		NP_001229796.1
KIR3DL2	XM_047438795.1	c.1034C>T	p.Thr345Met	missense_variant	7/7		XP_047294751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIR3DL2	ENST00000326321.7	c.1190C>T	p.Thr397Met	missense_variant	9/9	1	NM_006737.4	ENSP00000325525.3
KIR3DL2	ENST00000270442.5	c.1139C>T	p.Thr380Met	missense_variant	8/8	1		ENSP00000270442.5

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40294 AN: 151806 Hom.: 5997 Cov.: 31

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.282

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.283

GnomAD3 exomes AF: 0.316 AC: 79475 AN: 251458 Hom.: 13496 AF XY: 0.322 AC XY: 43800 AN XY: 135908

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.370

Gnomad ASJ exome AF: 0.346

Gnomad EAS exome AF: 0.283

Gnomad SAS exome AF: 0.387

Gnomad FIN exome AF: 0.330

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.325

GnomAD4 exome AF: 0.306 AC: 447281 AN: 1461746 Hom.: 71075 Cov.: 72 AF XY: 0.309 AC XY: 224785 AN XY: 727172

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.367

Gnomad4 ASJ exome AF: 0.344

Gnomad4 EAS exome AF: 0.289

Gnomad4 SAS exome AF: 0.384

Gnomad4 FIN exome AF: 0.336

Gnomad4 NFE exome AF: 0.301

Gnomad4 OTH exome AF: 0.310

GnomAD4 genome AF: 0.265 AC: 40318 AN: 151924 Hom.: 6010 Cov.: 31 AF XY: 0.272 AC XY: 20199 AN XY: 74236

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.344

Gnomad4 ASJ AF: 0.348

Gnomad4 EAS AF: 0.282

Gnomad4 SAS AF: 0.386

Gnomad4 FIN AF: 0.329

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.290

Alfa AF: 0.285 Hom.: 6588

Bravo AF: 0.257

TwinsUK AF: 0.303 AC: 1123

ALSPAC AF: 0.305 AC: 1177

ESP6500AA AF: 0.137 AC: 602

ESP6500EA AF: 0.295 AC: 2541

ExAC AF: 0.311 AC: 37801

Asia WGS AF: 0.373 AC: 1300 AN: 3478

EpiCase AF: 0.310

EpiControl AF: 0.311

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.0053	N
MetaRNN	Benign	0.0061	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.051
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.054	T;T
Polyphen		0.99	D;.
Vest4		0.066
MPC		0.0068
ClinPred		0.054	T
GERP RS		0.46
Varity_R		0.043
gMVP		0.21

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: rs3745902; hg19: chr19-55378008; COSMIC: COSV54391288; COSMIC: COSV54391288;