chr19-54852036-A-G

Position:

chr19-54852036-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_006737.4(KIR3DL2):c.109A>G(p.Thr37Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000528 in 1,609,940 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

KIR3DL2
NM_006737.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.943

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 Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015002161).

BP6

Variant 19-54852036-A-G is Benign according to our data. Variant chr19-54852036-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2601860.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KIR3DL2	NM_006737.4 linkuse as main transcript	c.109A>G	p.Thr37Ala	missense_variant	3/9	ENST00000326321.7
KIR3DL2	NM_001242867.2 linkuse as main transcript	c.109A>G	p.Thr37Ala	missense_variant	3/8
KIR3DL2	XM_047438795.1 linkuse as main transcript	c.109A>G	p.Thr37Ala	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIR3DL2	ENST00000326321.7 linkuse as main transcript	c.109A>G	p.Thr37Ala	missense_variant	3/9	1	NM_006737.4	P2	P43630-1
KIR3DL2	ENST00000270442.5 linkuse as main transcript	c.109A>G	p.Thr37Ala	missense_variant	3/8	1		A2	P43630-2

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151706

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000205

AC:

AN:

146448

Hom.:

AF XY:

0.00

AC XY:

AN XY:

80198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000147

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000151

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000562

AC:

AN:

1458116

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

725480

show subpopulations

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000127

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000586

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151824

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000921

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

Jun 29, 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

0.053

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.027

DANN

Benign

0.45

DEOGEN2

Benign

0.0015

T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0014

M_CAP

Benign

0.0012

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.52

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

1.3

N;N

REVEL

Benign

0.040

Sift

Benign

1.0

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.0

B;.

Vest4

0.031

MutPred

0.31

Loss of glycosylation at T37 (P = 0.0133);Loss of glycosylation at T37 (P = 0.0133);

MVP

0.081

MPC

1.7

ClinPred

0.045

GERP RS

-1.8

Varity_R

0.023

gMVP

0.10

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