19-54850501-C-T

Position:

chr19-54850501-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006737.4(KIR3DL2):c.26C>T(p.Ala9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,609,106 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0011 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 9 hom. )

Consequence

KIR3DL2
NM_006737.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.809

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05225718).

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIR3DL2	NM_006737.4 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	1/9	ENST00000326321.7	NP_006728.2	P43630-1A0A0U1WNF3Q8NHK6
KIR3DL2	NM_001242867.2 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	1/8		NP_001229796.1	P43630-2Q8NHI6
KIR3DL2	XM_047438795.1 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	1/7		XP_047294751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIR3DL2	ENST00000326321.7 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	1/9	1	NM_006737.4	ENSP00000325525.3		P43630-1
KIR3DL2	ENST00000270442.5 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	1/8	1		ENSP00000270442.5		P43630-2

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

165

AN:

151536

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000962

GnomAD3 exomes

AF:

0.0000464

AC:

AN:

129364

Hom.:

AF XY:

0.0000273

AC XY:

AN XY:

73140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000850

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

185

AN:

1457450

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

725182

show subpopulations

Gnomad4 AFR exome

AF:

0.00464

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.00109

AC:

166

AN:

151656

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

74168

show subpopulations

Gnomad4 AFR

AF:

0.00387

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000952

Alfa

AF:

0.000783

Hom.:

Bravo

AF:

0.00132

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000536

AC:

ExAC

AF:

0.0000281

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.26C>T (p.A9V) alteration is located in exon 1 (coding exon 1) of the KIR3DL2 gene. This alteration results from a C to T substitution at nucleotide position 26, causing the alanine (A) at amino acid position 9 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.5

DANN

Benign

0.88

DEOGEN2

Benign

0.010

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0037

M_CAP

Benign

0.00057

MetaRNN

Benign

0.052

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

2.0

M;M

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.040

Sift

Benign

0.055

T;T

Sift4G

Benign

1.0

T;T

Polyphen

1.0

D;.

Vest4

0.12

MVP

0.061

MPC

1.7

ClinPred

0.071

GERP RS

-1.7

Varity_R

0.041

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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