NM_016270.4:c.226C>A

Variant names:

• chr19-16325366-C-A
• rs901623443
• NM_016270.4:c.226C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016270.4(KLF2):​c.226C>A​(p.Pro76Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000233 in 1,288,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P76A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: KLF2 NM_016270.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.284
• Publications: 0 publications found

Genes affected

KLF2 (HGNC:6347): (KLF transcription factor 2) This gene encodes a protein that belongs to the Kruppel family of transcription factors. The encoded zinc finger protein is expressed early in mammalian development and is found in many different cell types. The protein acts to bind the CACCC box found in the promoter of target genes to activate their transcription. It plays a role in many processes during development and disease including adipogenesis, embryonic erythropoiesis, epithelial integrity, inflammation and t-cell viability. [provided by RefSeq, Mar 2017]

KLF2 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06803185).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016270.4. 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
	KLF2	NM_016270.4	MANE Select	c.226C>A	p.Pro76Thr	missense	Exon 2 of 3	NP_057354.1	Q9Y5W3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF2	ENST00000248071.6	TSL:1 MANE Select	c.226C>A	p.Pro76Thr	missense	Exon 2 of 3	ENSP00000248071.5	Q9Y5W3
	KLF2	ENST00000592003.1	TSL:3	c.75+368C>A		intron	N/A	ENSP00000465035.1	K7EJ60

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000233 AC: 3 AN: 1288128 Hom.: 0 Cov.: 33 AF XY: 0.00000315 AC XY: 2 AN XY: 635372

African (AFR) AF: 0.00 AC: 0 AN: 25202

American (AMR) AF: 0.00 AC: 0 AN: 16642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20032

East Asian (EAS) AF: 0.00 AC: 0 AN: 28966

South Asian (SAS) AF: 0.00 AC: 0 AN: 66332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4340

European-Non Finnish (NFE) AF: 0.00000288 AC: 3 AN: 1039918

Other (OTH) AF: 0.00 AC: 0 AN: 53076

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.28
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.039
Sift	Benign	0.43	T
Sift4G	Benign	0.074	T
Polyphen		0.0	B
Vest4		0.099
MutPred		0.28		Gain of phosphorylation at P76 (P = 0.0062)
MVP		0.27
MPC		1.9
ClinPred		0.072	T
GERP RS		0.80
Varity_R		0.11
gMVP		0.17
Mutation Taster		=94/6	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: rs901623443; hg19: chr19-16436177;