19-54852223-G-A

Position:

chr19-54852223-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_006737.4(KIR3DL2):c.296G>A(p.Arg99His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,611,058 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00040 ( 4 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

KIR3DL2
NM_006737.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.140

Variant links:

Genes affected

KIR3DL2 (HGNC:6339): (killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 2) 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. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2011]

KIR3DL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014616847).

BP6

Variant 19-54852223-G-A is Benign according to our data. Variant chr19-54852223-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2543683.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR3DL2	NM_006737.4 linkuse as main transcript	c.296G>A	p.Arg99His	missense_variant	3/9	ENST00000326321.7	NP_006728.2	P43630-1A0A0U1WNF3Q8NHK6
KIR3DL2	NM_001242867.2 linkuse as main transcript	c.296G>A	p.Arg99His	missense_variant	3/8		NP_001229796.1	P43630-2Q8NHI6
KIR3DL2	XM_047438795.1 linkuse as main transcript	c.296G>A	p.Arg99His	missense_variant	3/7		XP_047294751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIR3DL2	ENST00000326321.7 linkuse as main transcript	c.296G>A	p.Arg99His	missense_variant	3/9	1	NM_006737.4	ENSP00000325525.3		P43630-1
KIR3DL2	ENST00000270442.5 linkuse as main transcript	c.296G>A	p.Arg99His	missense_variant	3/8	1		ENSP00000270442.5		P43630-2

Frequencies

GnomAD3 genomes

AF:

0.000330

AC:

AN:

151390

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000810

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.0000732

AC:

AN:

232174

Hom.:

AF XY:

0.0000639

AC XY:

AN XY:

125286

show subpopulations

Gnomad AFR exome

AF:

0.000573

Gnomad AMR exome

AF:

0.0000623

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000188

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.0000993

AC:

145

AN:

1459554

Hom.:

Cov.:

AF XY:

0.0000978

AC XY:

AN XY:

726042

show subpopulations

Gnomad4 AFR exome

AF:

0.000781

Gnomad4 AMR exome

AF:

0.0000897

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000837

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000396

AC:

AN:

151504

Hom.:

Cov.:

AF XY:

0.000351

AC XY:

AN XY:

74062

show subpopulations

Gnomad4 AFR

AF:

0.00105

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000950

Alfa

AF:

0.000253

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.0000432

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.9

DANN

Benign

0.47

DEOGEN2

Benign

0.0021

T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.00011

M_CAP

Benign

0.00083

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.4

N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

3.7

N;N

REVEL

Benign

0.022

Sift

Benign

1.0

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.0

B;.

Vest4

0.071

MVP

0.099

MPC

2.0

ClinPred

0.012

GERP RS

-0.99

Varity_R

0.026

gMVP

0.056

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over