rs12505758

Variant names:

• chr4-55100731-T-C
• rs12505758
• NM_002253.4:c.2266+1166A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002253.4(KDR):​c.2266+1166A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,170 control chromosomes in the GnomAD database, including 1,213 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 0.11 (1213 hom., cov: 32)
• Consequence: KDR NM_002253.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0950
• Publications: 13 publications found

Genes affected

KDR (HGNC:6307): (kinase insert domain receptor) Vascular endothelial growth factor (VEGF) is a major growth factor for endothelial cells. This gene encodes one of the two receptors of the VEGF. This receptor, known as kinase insert domain receptor, is a type III receptor tyrosine kinase. It functions as the main mediator of VEGF-induced endothelial proliferation, survival, migration, tubular morphogenesis and sprouting. The signalling and trafficking of this receptor are regulated by multiple factors, including Rab GTPase, P2Y purine nucleotide receptor, integrin alphaVbeta3, T-cell protein tyrosine phosphatase, etc.. Mutations of this gene are implicated in infantile capillary hemangiomas. [provided by RefSeq, May 2009]

KDR Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDR	NM_002253.4	c.2266+1166A>G		intron_variant	Intron 15 of 29	ENST00000263923.5	NP_002244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDR	ENST00000263923.5	c.2266+1166A>G		intron_variant	Intron 15 of 29	1	NM_002253.4	ENSP00000263923.4
KDR	ENST00000647068.1	n.2279+1166A>G		intron_variant	Intron 15 of 29

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16179 AN: 152054 Hom.: 1217 Cov.: 32

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.0813

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.121

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.106 AC: 16165 AN: 152170 Hom.: 1213 Cov.: 32 AF XY: 0.108 AC XY: 8064 AN XY: 74390

African (AFR) AF: 0.0314 AC: 1304 AN: 41552

American (AMR) AF: 0.126 AC: 1916 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 884 AN: 3470

East Asian (EAS) AF: 0.205 AC: 1062 AN: 5178

South Asian (SAS) AF: 0.335 AC: 1612 AN: 4810

European-Finnish (FIN) AF: 0.0813 AC: 861 AN: 10594

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8147 AN: 67982

Other (OTH) AF: 0.122 AC: 258 AN: 2114

Alfa AF: 0.123 Hom.: 698

Bravo AF: 0.103

Asia WGS AF: 0.264 AC: 920 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.2
DANN	Benign	0.65
PhyloP100		-0.095
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12505758; hg19: chr4-55966898;