19-54741976-C-T

Variant names:

• chr19-54741976-C-T
• rs193921051
• NM_015868.3:c.71-4C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015868.3(KIR2DL3):​c.71-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 112,370 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (2 hom., cov: 28)
  • Exomes 𝑓: 0.17 (44 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIR2DL3 NM_015868.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003298
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -1.19
• Publications: 1 publications found

Genes affected

KIR2DL3 (HGNC:6331): (killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3) 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIR2DL3	NM_015868.3	c.71-4C>T		splice_region_variant, intron_variant	Intron 2 of 7	ENST00000342376.4	NP_056952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIR2DL3	ENST00000342376.4	c.71-4C>T		splice_region_variant, intron_variant	Intron 2 of 7	1	NM_015868.3	ENSP00000342215.3
ENSG00000215765	ENST00000400864.3	n.35+17446C>T		intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes AF: 0.122 AC: 13673 AN: 112272 Hom.: 2 Cov.: 28

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0865

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.0486

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.0958

Gnomad MID AF: 0.183

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.126

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.169 AC: 189717 AN: 1125568 Hom.: 44 Cov.: 31 AF XY: 0.171 AC XY: 95199 AN XY: 557030

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

African (AFR) AF: 0.146 AC: 3883 AN: 26602

American (AMR) AF: 0.156 AC: 5558 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 4395 AN: 19626

East Asian (EAS) AF: 0.0461 AC: 1629 AN: 35364

South Asian (SAS) AF: 0.249 AC: 15363 AN: 61702

European-Finnish (FIN) AF: 0.117 AC: 4752 AN: 40606

Middle Eastern (MID) AF: 0.235 AC: 811 AN: 3450

European-Non Finnish (NFE) AF: 0.170 AC: 145325 AN: 856700

Other (OTH) AF: 0.175 AC: 8001 AN: 45840

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.122 AC: 13688 AN: 112370 Hom.: 2 Cov.: 28 AF XY: 0.122 AC XY: 6706 AN XY: 54944

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

African (AFR) AF: 0.105 AC: 3302 AN: 31426

American (AMR) AF: 0.141 AC: 1545 AN: 10920

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 436 AN: 2446

East Asian (EAS) AF: 0.0487 AC: 220 AN: 4516

South Asian (SAS) AF: 0.195 AC: 641 AN: 3284

European-Finnish (FIN) AF: 0.0958 AC: 779 AN: 8134

Middle Eastern (MID) AF: 0.194 AC: 40 AN: 206

European-Non Finnish (NFE) AF: 0.131 AC: 6474 AN: 49298

Other (OTH) AF: 0.130 AC: 196 AN: 1504

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.118 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Prostate cancer Uncertain:1

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Science for Life laboratory, Karolinska Institutet

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.58
DANN	Benign	0.54
PhyloP100		-1.2
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.040		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: rs193921051; hg19: chr19-55253422; COSMIC: COSV60898587;