19-54806214-C-G

Variant names:

• chr19-54806214-C-G
• rs1051456
• NM_001080770.2:c.625C>G

Variant summary

Our verdict is Benign. The variant received -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. 12/19 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P209L) has been classified as Uncertain significance.

• 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
• Publications: 17 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080770.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIR2DL4	NM_001080770.2	MANE Select	c.625C>G	p.Pro209Ala	missense	Exon 4 of 7	NP_001074239.1	Q99706-3
	KIR2DL4	NM_001080772.2		c.625C>G	p.Pro209Ala	missense	Exon 4 of 8	NP_001074241.1	A0A0B4J1S6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIR2DL4	ENST00000345540.10	TSL:1 MANE Select	c.625C>G	p.Pro209Ala	missense	Exon 4 of 7	ENSP00000339634.5	Q99706-3
	KIR2DL4	ENST00000357494.8	TSL:1	c.625C>G	p.Pro209Ala	missense	Exon 4 of 6	ENSP00000350088.4	Q99706-4
	KIR2DL4	ENST00000359085.8	TSL:1	c.625C>G	p.Pro209Ala	missense	Exon 4 of 8	ENSP00000351988.4	A0A0B4J1S6

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

GnomAD2 exomes AF: 0.466 AC: 6584 AN: 14122 AF XY: 0.454

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.525 AC: 17266 AN: 32896

American (AMR) AF: 0.415 AC: 18438 AN: 44434

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7221 AN: 25818

East Asian (EAS) AF: 0.499 AC: 19646 AN: 39400

South Asian (SAS) AF: 0.258 AC: 21817 AN: 84660

European-Finnish (FIN) AF: 0.230 AC: 11987 AN: 52006

Middle Eastern (MID) AF: 0.285 AC: 1621 AN: 5682

European-Non Finnish (NFE) AF: 0.255 AC: 278440 AN: 1090160

Other (OTH) AF: 0.283 AC: 16834 AN: 59502

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.511 AC: 20392 AN: 39940

American (AMR) AF: 0.332 AC: 4975 AN: 14968

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 910 AN: 3404

East Asian (EAS) AF: 0.496 AC: 2517 AN: 5072

South Asian (SAS) AF: 0.250 AC: 1158 AN: 4624

European-Finnish (FIN) AF: 0.235 AC: 2427 AN: 10328

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 16907 AN: 67318

Other (OTH) AF: 0.309 AC: 636 AN: 2060

Alfa AF: 0.0189 Hom.: 14

ExAC AF: 0.238 AC: 758

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
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
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.40
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.047
Sift	Benign	0.083	T
Sift4G	Uncertain	0.031	D
Polyphen		0.99	D
Vest4		0.063
MPC		1.6
ClinPred		0.033	T
GERP RS		-0.16
gMVP		0.016
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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