rs1406390812

Variant names:

• chr19-16325570-C-T
• rs1406390812
• NM_016270.4:c.430C>T

Variant summary

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

The NM_016270.4(KLF2):​c.430C>T​(p.Pro144Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,170,304 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (4 hom.)
• Consequence: KLF2 NM_016270.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046927124).
• BS2: High AC in GnomAd4 at 16 AD gene.

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.430C>T	p.Pro144Ser	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.430C>T	p.Pro144Ser	missense	Exon 2 of 3	ENSP00000248071.5	Q9Y5W3
	KLF2	ENST00000592003.1	TSL:3	c.75+572C>T		intron	N/A	ENSP00000465035.1	K7EJ60

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 16 AN: 149012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000668

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.000486

GnomAD4 exome AF: 0.000102 AC: 104 AN: 1021184 Hom.: 4 Cov.: 33 AF XY: 0.000124 AC XY: 60 AN XY: 482434

African (AFR) AF: 0.00 AC: 0 AN: 20340

American (AMR) AF: 0.00 AC: 0 AN: 6260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11332

East Asian (EAS) AF: 0.00 AC: 0 AN: 20984

South Asian (SAS) AF: 0.00363 AC: 71 AN: 19558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18562

Middle Eastern (MID) AF: 0.000390 AC: 1 AN: 2562

European-Non Finnish (NFE) AF: 0.0000295 AC: 26 AN: 882566

Other (OTH) AF: 0.000154 AC: 6 AN: 39020

GnomAD4 genome AF: 0.000107 AC: 16 AN: 149120 Hom.: 0 Cov.: 32 AF XY: 0.000137 AC XY: 10 AN XY: 72774

African (AFR) AF: 0.00 AC: 0 AN: 41190

American (AMR) AF: 0.0000667 AC: 1 AN: 14996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66856

Other (OTH) AF: 0.000481 AC: 1 AN: 2080

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.018
Sift	Benign	0.49	T
Sift4G	Benign	0.20	T
Polyphen		0.0050	B
Vest4		0.20
MutPred		0.26		Gain of phosphorylation at P144 (P = 0.0051)
MVP		0.32
MPC		2.6
ClinPred		0.25	T
GERP RS		1.7
Varity_R		0.041
gMVP		0.37
Mutation Taster		=97/3	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: rs1406390812; hg19: chr19-16436381;