19-54783763-A-G

Variant names:

• chr19-54783763-A-G
• rs2756923
• NM_014218.3:c.997A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014218.3(KIR2DL1):​c.997A>G​(p.Thr333Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,604,402 control chromosomes in the GnomAD database, including 2,106 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (254 hom., cov: 33)
  • Exomes 𝑓: 0.15 (1852 hom.)
• Consequence: KIR2DL1 NM_014218.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.983

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]

ENSG00000215765 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002367258).
• BP6: Variant 19-54783763-A-G is Benign according to our data. Variant chr19-54783763-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3060390.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIR2DL1	NM_014218.3	c.997A>G	p.Thr333Ala	missense_variant	Exon 8 of 8	ENST00000336077.11	NP_055033.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIR2DL1	ENST00000336077.11	c.997A>G	p.Thr333Ala	missense_variant	Exon 8 of 8	1	NM_014218.3	ENSP00000336769.5
KIR2DL1	ENST00000291633.7	c.1075A>G	p.Thr359Ala	missense_variant	Exon 9 of 9	1		ENSP00000291633.7
ENSG00000215765	ENST00000400864.3	n.72-2700A>G		intron_variant	Intron 2 of 5	5

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23003 AN: 150592 Hom.: 252 Cov.: 33

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.0293

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.162

GnomAD4 exome AF: 0.148 AC: 215318 AN: 1453690 Hom.: 1852 Cov.: 71 AF XY: 0.153 AC XY: 110547 AN XY: 723368

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.0206

Gnomad4 SAS exome AF: 0.258

Gnomad4 FIN exome AF: 0.145

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.153 AC: 23023 AN: 150712 Hom.: 254 Cov.: 33 AF XY: 0.155 AC XY: 11417 AN XY: 73620

Gnomad4 AFR AF: 0.163

Gnomad4 AMR AF: 0.142

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.0292

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.166

Alfa AF: 0.0750 Hom.: 8

ExAC AF: 0.0000896 AC: 9

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

KIR2DL1-related disorder Benign:1

Aug 09, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.57
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00059	N
M_CAP	Benign	0.00041	T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.010
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.71	T;T
Polyphen		0.017	B;.
Vest4		0.034
MutPred		0.23		.;Gain of sheet (P = 0.0221);
MVP		0.34
MPC		1.8
ClinPred		0.0032	T
GERP RS		-1.8
gMVP		0.026

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: rs2756923; hg19: chr19-55295215;