19-54806214-C-G

Position:

• chr19-54806214-C-G

Variant summary

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

The NM_001080770.2(KIR2DL4):​c.625C>G​(p.Pro209Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,583,472 control chromosomes in the GnomAD database, including 71,690 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.34 (9954 hom., cov: 29)
  • Exomes 𝑓: 0.27 (61736 hom.)
• Consequence: KIR2DL4 NM_001080770.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.400

Genes affected

KIR2DL4 (HGNC:6332): (killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 4) 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. Alternate alleles of this gene are represented on multiple alternate reference loci (ALT_REF_LOCs). Alternative splicing results in multiple transcript variants, some of which may not be annotated on the primary reference assembly. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.8435581E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR2DL4	NM_001080770.2	c.625C>G	p.Pro209Ala	missense_variant	4/7	ENST00000345540.10	NP_001074239.1
KIR2DL4	NM_001080772.2	c.625C>G	p.Pro209Ala	missense_variant	4/8		NP_001074241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIR2DL4	ENST00000345540.10	c.625C>G	p.Pro209Ala	missense_variant	4/7	1	NM_001080770.2	ENSP00000339634.5

Frequencies

GnomAD3 genomes AF: 0.337 AC: 50142 AN: 148796 Hom.: 9930 Cov.: 29

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.496

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.314

GnomAD3 exomes AF: 0.466 AC: 6584 AN: 14122 Hom.: 1722 AF XY: 0.454 AC XY: 3298 AN XY: 7264

Gnomad AFR exome AF: 0.614

Gnomad AMR exome AF: 0.523

Gnomad ASJ exome AF: 0.413

Gnomad EAS exome AF: 0.709

Gnomad SAS exome AF: 0.400

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.343

GnomAD4 exome AF: 0.274 AC: 393270 AN: 1434558 Hom.: 61736 Cov.: 38 AF XY: 0.272 AC XY: 193993 AN XY: 713826

Gnomad4 AFR exome AF: 0.525

Gnomad4 AMR exome AF: 0.415

Gnomad4 ASJ exome AF: 0.280

Gnomad4 EAS exome AF: 0.499

Gnomad4 SAS exome AF: 0.258

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.255

Gnomad4 OTH exome AF: 0.283

GnomAD4 genome AF: 0.337 AC: 50215 AN: 148914 Hom.: 9954 Cov.: 29 AF XY: 0.335 AC XY: 24308 AN XY: 72604

Gnomad4 AFR AF: 0.511

Gnomad4 AMR AF: 0.332

Gnomad4 ASJ AF: 0.267

Gnomad4 EAS AF: 0.496

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.235

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.309

Alfa AF: 0.0189 Hom.: 14

ExAC AF: 0.238 AC: 758

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.54
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0063	N
MetaRNN	Benign	0.0000028	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.1	.;.;M;M;.;.
PROVEAN	Pathogenic	-4.7	.;D;D;D;D;D
REVEL	Benign	0.047
Sift	Benign	0.083	.;T;T;T;T;T
Sift4G	Uncertain	0.031	D;D;D;D;T;T
Polyphen		0.99, 0.99, 0.66	.;.;D;D;.;P
Vest4		0.063
MPC		1.6
ClinPred		0.033	T
GERP RS		-0.16
gMVP		0.016

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: rs1051456; hg19: chr19-55317669; COSMIC: COSV60877458;