rs2241524

chr19-54587200-G-Achr19-54587200-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PVS1_Strong BA1

The NM_001130917.3(LILRA2):c.1307-1G>A variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,613,466 control chromosomes in the GnomAD database, including 3,515 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.037 (403 hom., cov: 32)
  • Exomes 𝑓: 0.025 (3112 hom.)
• Consequence: LILRA2 NM_001130917.3 splice_acceptor
• Scores: Splicing: ADA: 0.9973
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.64

Genes affected

LILRA2 (HGNC:6603): (leukocyte immunoglobulin like receptor A2) This gene encodes a member of a family of immunoreceptors that are expressed predominantly on monocytes and B cells, and at lower levels on dendritic cells and natural killer cells. The encoded protein is an activating receptor that inhibits dendritic cell differentiation and antigen presentation and suppresses innate immune response. Alternatively spliced transcript variants encoding different isoforms have been found. This gene is located in a cluster of related genes on chromosome 19 and there is a pseudogene for this gene on chromosome 3. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.53133607 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.5, offset of 9, new splice context is: tctttgtccaacatccctAGgcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LILRA2	NM_001130917.3	c.1307-1G>A		splice_acceptor_variant		ENST00000391738.8
LILRA2	NM_001290270.1	c.1220-1G>A		splice_acceptor_variant
LILRA2	NM_001290271.2	c.*42-1G>A		splice_acceptor_variant
LILRA2	NM_006866.4	c.1256-1G>A		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LILRA2	ENST00000391738.8	c.1307-1G>A		splice_acceptor_variant		1	NM_001130917.3	P4

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5609 AN: 152048 Hom.: 404 Cov.: 32

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.0488

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00906

Gnomad OTH AF: 0.0345

GnomAD3 exomes AF: 0.0662 AC: 16402 AN: 247804 Hom.: 1795 AF XY: 0.0579 AC XY: 7714 AN XY: 133320

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.298

Gnomad SAS exome AF: 0.0431

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.00965

Gnomad OTH exome AF: 0.0425

GnomAD4 exome AF: 0.0248 AC: 36177 AN: 1461300 Hom.: 3112 Cov.: 32 AF XY: 0.0243 AC XY: 17630 AN XY: 726916

Gnomad4 AFR exome AF: 0.0281

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.0111

Gnomad4 EAS exome AF: 0.299

Gnomad4 SAS exome AF: 0.0377

Gnomad4 FIN exome AF: 0.0153

Gnomad4 NFE exome AF: 0.00711

Gnomad4 OTH exome AF: 0.0308

GnomAD4 genome AF: 0.0370 AC: 5623 AN: 152166 Hom.: 403 Cov.: 32 AF XY: 0.0403 AC XY: 3001 AN XY: 74400

Gnomad4 AFR AF: 0.0294

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.291

Gnomad4 SAS AF: 0.0486

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.00906

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.0106 Hom.: 20

Bravo AF: 0.0487

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.0334 AC: 147

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.0576 AC: 6994

EpiCase AF: 0.00889

EpiControl AF: 0.0108

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.99	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	1.1
Dann	Benign	0.50
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.0023	N
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
GERP RS		-2.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.80		Position offset: 10
DS_AL_spliceai		0.76		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2241524; hg19: chr19-55098667; COSMIC: COSV52189668; COSMIC: COSV52189668;