19-54769863-G-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 11/18 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 0.21 (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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIR2DL1	NM_014218.3	c.13G>T	p.Val5Phe	missense_variant	Exon 1 of 8	ENST00000336077.11	NP_055033.2
LOC101928804	NR_110737.1	n.340C>A		non_coding_transcript_exon_variant	Exon 3 of 3
LOC101928804	NR_110738.1	n.269C>A		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIR2DL1	ENST00000336077.11	c.13G>T	p.Val5Phe	missense_variant	Exon 1 of 8	1	NM_014218.3	ENSP00000336769.5
KIR2DL1	ENST00000291633.7	c.13G>T	p.Val5Phe	missense_variant	Exon 1 of 9	1		ENSP00000291633.7
ENSG00000215765	ENST00000400864.3	n.36-986G>T		intron_variant	Intron 1 of 5	5

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

GnomAD3 exomes AF: 0.236 AC: 57224 AN: 242914 Hom.: 13711 AF XY: 0.238 AC XY: 31211 AN XY: 131342

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 SAS exome AF: 0.128

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

Gnomad4 AFR exome AF: 0.0895

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.233

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.319

Gnomad4 NFE exome AF: 0.306

Gnomad4 OTH exome AF: 0.242

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

Gnomad4 AFR AF: 0.0997

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.115

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.314

Gnomad4 NFE AF: 0.295

Gnomad4 OTH AF: 0.210

Alfa AF: 0.164 Hom.: 973

ESP6500AA AF: 0.106 AC: 457

ESP6500EA AF: 0.312 AC: 2620

ExAC AF: 0.235 AC: 28000

Asia WGS AF: 0.116 AC: 394 AN: 3398

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T
MetaSVM	Benign	-0.93	T
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.033
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.75	P;.
Vest4		0.14
MPC		1.2
ClinPred		0.0090	T
GERP RS		-1.0
gMVP		0.14

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: rs2304224; hg19: chr19-55281315; COSMIC: COSV52409559; COSMIC: COSV52409559;