rs631717

Positions:

• chr19-54811520-G-A

Variant summary

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

The NM_001080770.2(KIR2DL4):​c.707-2170G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 150,198 control chromosomes in the GnomAD database, including 21,671 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.

• Frequency: Genomes: 𝑓 0.52 (21671 hom., cov: 30)
• Consequence: KIR2DL4 NM_001080770.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0550

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 (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR2DL4	NM_001080770.2	c.707-2170G>A		intron_variant		ENST00000345540.10	NP_001074239.1
KIR2DL4	NM_001080772.2	c.707-1605G>A		intron_variant			NP_001074241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIR2DL4	ENST00000345540.10	c.707-2170G>A		intron_variant		1	NM_001080770.2	ENSP00000339634	A2

Frequencies

GnomAD3 genomes AF: 0.525 AC: 78759 AN: 150084 Hom.: 21636 Cov.: 30

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.521

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.525 AC: 78837 AN: 150198 Hom.: 21671 Cov.: 30 AF XY: 0.533 AC XY: 39045 AN XY: 73270

Gnomad4 AFR AF: 0.589

Gnomad4 AMR AF: 0.573

Gnomad4 ASJ AF: 0.503

Gnomad4 EAS AF: 0.712

Gnomad4 SAS AF: 0.578

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.465

Gnomad4 OTH AF: 0.521

Alfa AF: 0.491 Hom.: 4611

Bravo AF: 0.539

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	5.0
DANN	Benign	0.46

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: rs631717; hg19: chr19-55322975;