chr19-54813180-T-C

Variant names:

• chr19-54813180-T-C
• rs649216
• ENST00000359085.8:c.762T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001080772.2(KIR2DL4):​c.762T>C​(p.Phe254Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 1,362,288 control chromosomes in the GnomAD database, including 208,821 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.52 (17084 hom., cov: 18)
  • Exomes 𝑓: 0.52 (191737 hom.)
• Consequence: KIR2DL4 NM_001080772.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.616
• Publications: 29 publications found

Genes affected

KIR2DL4 (HGNC:6332): (killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 4) 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. Alternate alleles of this gene are represented on multiple alternate reference loci (ALT_REF_LOCs). Alternative splicing results in multiple transcript variants, some of which may not be annotated on the primary reference assembly. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 17084 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080772.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIR2DL4	NM_001080770.2	MANE Select	c.707-510T>C		intron	N/A	NP_001074239.1	Q99706-3
	KIR2DL4	NM_001080772.2		c.762T>C	p.Phe254Phe	synonymous	Exon 6 of 8	NP_001074241.1	A0A0B4J1S6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIR2DL4	ENST00000359085.8	TSL:1	c.762T>C	p.Phe254Phe	synonymous	Exon 6 of 8	ENSP00000351988.4	A0A0B4J1S6
	KIR2DL4	ENST00000345540.10	TSL:1 MANE Select	c.707-510T>C		intron	N/A	ENSP00000339634.5	Q99706-3
	KIR2DL4	ENST00000357494.8	TSL:1	c.656-510T>C		intron	N/A	ENSP00000350088.4	Q99706-4

Frequencies

GnomAD3 genomes AF: 0.518 AC: 61234 AN: 118196 Hom.: 17063 Cov.: 18

Gnomad AFR AF: 0.622

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.539

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.525

GnomAD2 exomes AF: 0.0115 AC: 1724 AN: 150032 AF XY: 0.00887

Gnomad AFR exome AF: 0.0335

Gnomad AMR exome AF: 0.00766

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.0240

Gnomad FIN exome AF: 0.00373

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00772

GnomAD4 exome AF: 0.517 AC: 643528 AN: 1244026 Hom.: 191737 Cov.: 31 AF XY: 0.519 AC XY: 322292 AN XY: 620722

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

African (AFR) AF: 0.705 AC: 19212 AN: 27248

American (AMR) AF: 0.691 AC: 26223 AN: 37974

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 12812 AN: 23226

East Asian (EAS) AF: 0.831 AC: 29750 AN: 35798

South Asian (SAS) AF: 0.609 AC: 47170 AN: 77444

European-Finnish (FIN) AF: 0.498 AC: 22207 AN: 44636

Middle Eastern (MID) AF: 0.520 AC: 2311 AN: 4442

European-Non Finnish (NFE) AF: 0.484 AC: 455838 AN: 941360

Other (OTH) AF: 0.540 AC: 28005 AN: 51898

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.518 AC: 61276 AN: 118262 Hom.: 17084 Cov.: 18 AF XY: 0.517 AC XY: 29189 AN XY: 56474

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

African (AFR) AF: 0.622 AC: 16941 AN: 27246

American (AMR) AF: 0.531 AC: 5954 AN: 11222

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1496 AN: 2950

East Asian (EAS) AF: 0.777 AC: 3040 AN: 3912

South Asian (SAS) AF: 0.553 AC: 1999 AN: 3618

European-Finnish (FIN) AF: 0.430 AC: 3264 AN: 7596

Middle Eastern (MID) AF: 0.527 AC: 137 AN: 260

European-Non Finnish (NFE) AF: 0.462 AC: 27273 AN: 59030

Other (OTH) AF: 0.527 AC: 864 AN: 1638

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.532 Hom.: 7034

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	15
DANN	Benign	0.49
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: 48

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

Other links and lift over

dbSNP: rs649216; hg19: chr19-55324635; COSMIC: COSV58487431; COSMIC: COSV58487431;