19-54783763-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 15/20 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
• Publications: 10 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]

ENSG00000215765 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 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 VariationId is 3060390.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 254 AR gene

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

GnomAD2 exomes AF: 0.000267 AC: 33 AN: 123566 AF XY: 0.000183

Gnomad AFR exome AF: 0.00257

Gnomad AMR exome AF: 0.000259

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000583

Gnomad OTH exome AF: 0.00

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

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

African (AFR) AF: 0.163 AC: 5387 AN: 32980

American (AMR) AF: 0.101 AC: 4499 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5078 AN: 26090

East Asian (EAS) AF: 0.0206 AC: 819 AN: 39674

South Asian (SAS) AF: 0.258 AC: 22112 AN: 85768

European-Finnish (FIN) AF: 0.145 AC: 7712 AN: 53344

Middle Eastern (MID) AF: 0.230 AC: 1322 AN: 5738

European-Non Finnish (NFE) AF: 0.144 AC: 158623 AN: 1105334

Other (OTH) AF: 0.163 AC: 9766 AN: 60078

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

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

African (AFR) AF: 0.163 AC: 6654 AN: 40922

American (AMR) AF: 0.142 AC: 2148 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 635 AN: 3442

East Asian (EAS) AF: 0.0292 AC: 151 AN: 5178

South Asian (SAS) AF: 0.251 AC: 1184 AN: 4722

European-Finnish (FIN) AF: 0.146 AC: 1525 AN: 10440

Middle Eastern (MID) AF: 0.221 AC: 64 AN: 290

European-Non Finnish (NFE) AF: 0.151 AC: 10209 AN: 67530

Other (OTH) AF: 0.166 AC: 349 AN: 2102

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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
LIST_S2	Benign	0.0	.;.
M_CAP	Benign	0.00041	T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	.;.
PhyloP100		-0.98
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
Vest4		0.034
ClinPred		0.0032	T
GERP RS		-1.8
gMVP		0.026
Mutation Taster		=100/0	polymorphism

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: rs2756923; hg19: chr19-55295215; COSMIC: COSV108083096;