19-54769863-G-T

Variant names:

• chr19-54769863-G-T
• rs2304224
• NM_014218.3:c.13G>T
• KIR2DL1 p.Val5Phe

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014218.3(KIR2DL1):​c.13G>T​(p.Val5Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,558,442 control chromosomes in the GnomAD database, including 90,203 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.

• Frequency:
  • Genomes: 𝑓 0.21 (5735 hom., cov: 31)
  • Exomes 𝑓: 0.27 (84468 hom.)
• Consequence: KIR2DL1 NM_014218.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.885
• Publications: 15 publications found

Genes affected

KIR2DL1 (HGNC:6329): (killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1) 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]

LOC101928804 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010675669).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014218.3. 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
	KIR2DL1	NM_014218.3	MANE Select	c.13G>T	p.Val5Phe	missense	Exon 1 of 8	NP_055033.2	P43626-1
	LOC101928804	NR_110737.1		n.340C>A		non_coding_transcript_exon	Exon 3 of 3
	LOC101928804	NR_110738.1		n.269C>A		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIR2DL1	ENST00000336077.11	TSL:1 MANE Select	c.13G>T	p.Val5Phe	missense	Exon 1 of 8	ENSP00000336769.5	P43626-1
	KIR2DL1	ENST00000291633.7	TSL:1	c.13G>T	p.Val5Phe	missense	Exon 1 of 9	ENSP00000291633.7	P43626-2
	KIR2DL1	ENST00000885740.1		c.13G>T	p.Val5Phe	missense	Exon 1 of 7	ENSP00000555799.1

Frequencies

GnomAD3 genomes AF: 0.214 AC: 31172 AN: 145496 Hom.: 5735 Cov.: 31

Gnomad AFR AF: 0.0998

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.212

GnomAD2 exomes AF: 0.236 AC: 57224 AN: 242914 AF XY: 0.238

Gnomad AFR exome AF: 0.0994

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.118

Gnomad FIN exome AF: 0.346

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.255

GnomAD4 exome AF: 0.274 AC: 387499 AN: 1412828 Hom.: 84468 Cov.: 40 AF XY: 0.270 AC XY: 189747 AN XY: 703284

African (AFR) AF: 0.0895 AC: 2945 AN: 32910

American (AMR) AF: 0.118 AC: 5119 AN: 43486

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 5741 AN: 24650

East Asian (EAS) AF: 0.103 AC: 4070 AN: 39418

South Asian (SAS) AF: 0.121 AC: 10245 AN: 84502

European-Finnish (FIN) AF: 0.319 AC: 16232 AN: 50904

Middle Eastern (MID) AF: 0.190 AC: 1061 AN: 5592

European-Non Finnish (NFE) AF: 0.306 AC: 327945 AN: 1072930

Other (OTH) AF: 0.242 AC: 14141 AN: 58436

GnomAD4 genome AF: 0.214 AC: 31170 AN: 145614 Hom.: 5735 Cov.: 31 AF XY: 0.210 AC XY: 14889 AN XY: 70946

African (AFR) AF: 0.0997 AC: 4019 AN: 40328

American (AMR) AF: 0.159 AC: 2252 AN: 14192

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 728 AN: 3268

East Asian (EAS) AF: 0.115 AC: 586 AN: 5088

South Asian (SAS) AF: 0.124 AC: 569 AN: 4580

European-Finnish (FIN) AF: 0.314 AC: 3157 AN: 10060

Middle Eastern (MID) AF: 0.246 AC: 70 AN: 284

European-Non Finnish (NFE) AF: 0.295 AC: 19134 AN: 64930

Other (OTH) AF: 0.210 AC: 422 AN: 2014

Alfa AF: 0.164 Hom.: 973

Asia WGS AF: 0.116 AC: 394 AN: 3398

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0026	N
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.89
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.033
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0060	D
PromoterAI		0.056	Neutral
gMVP		0.14
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2304224;

hg19: chr19-55281315;

COSMIC: COSV52409559;

COSMIC: COSV52409559;