NM_002253.4:c.2066C>T

Variant names:

• chr4-55102430-G-A
• rs34038364
• NM_002253.4:c.2066C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002253.4(KDR):​c.2066C>T​(p.Thr689Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,613,602 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (12 hom.)
• Consequence: KDR NM_002253.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3 O:1
• Conservation: PhyloP100: -0.0930
• Publications: 15 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052033663).
• BP6: Variant 4-55102430-G-A is Benign according to our data. Variant chr4-55102430-G-A is described in ClinVar as Benign. ClinVar VariationId is 134606.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 443 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002253.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDR	NM_002253.4	MANE Select	c.2066C>T	p.Thr689Met	missense	Exon 14 of 30	NP_002244.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDR	ENST00000263923.5	TSL:1 MANE Select	c.2066C>T	p.Thr689Met	missense	Exon 14 of 30	ENSP00000263923.4
	KDR	ENST00000647068.1		n.2079C>T		non_coding_transcript_exon	Exon 14 of 30

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 443 AN: 152138 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00319 AC: 800 AN: 251160 AF XY: 0.00297

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.00296

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00336 AC: 4916 AN: 1461346 Hom.: 12 Cov.: 32 AF XY: 0.00322 AC XY: 2344 AN XY: 726994

African (AFR) AF: 0.000389 AC: 13 AN: 33446

American (AMR) AF: 0.00242 AC: 108 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.0136 AC: 724 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.00349 AC: 3880 AN: 1111600

Other (OTH) AF: 0.00310 AC: 187 AN: 60364

GnomAD4 genome AF: 0.00291 AC: 443 AN: 152256 Hom.: 1 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74440

African (AFR) AF: 0.000770 AC: 32 AN: 41564

American (AMR) AF: 0.00242 AC: 37 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0138 AC: 146 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00322 AC: 219 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00282 Hom.: 1

Bravo AF: 0.00209

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00287 AC: 349

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00327

EpiControl AF: 0.00344

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Hirschsprung disease, susceptibility to, 1 (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.5
DANN	Benign	0.87
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.093
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.044
Sift	Benign	0.14	T
Sift4G	Benign	0.12	T
Polyphen		0.025	B
Vest4		0.22
MVP		0.082
MPC		0.17
ClinPred		0.0020	T
GERP RS		3.3
Varity_R		0.13
gMVP		0.43
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs34038364; hg19: chr4-55968597; COSMIC: COSV55779992; COSMIC: COSV55779992;