rs3745318

Variant names:

• chr19-16325451-T-C
• rs3745318
• NM_016270.4:c.311T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016270.4(KLF2):​c.311T>C​(p.Leu104Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.76 in 1,405,660 control chromosomes in the GnomAD database, including 409,575 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L104V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.81 (51016 hom., cov: 33)
  • Exomes 𝑓: 0.75 (358559 hom.)
• Consequence: KLF2 NM_016270.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.813

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.106354E-7).
• BP6: Variant 19-16325451-T-C is Benign according to our data. Variant chr19-16325451-T-C is described in ClinVar as [Benign]. Clinvar id is 1177685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.941 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF2	NM_016270.4	c.311T>C	p.Leu104Pro	missense_variant	Exon 2 of 3	ENST00000248071.6	NP_057354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLF2	ENST00000248071.6	c.311T>C	p.Leu104Pro	missense_variant	Exon 2 of 3	1	NM_016270.4	ENSP00000248071.5
KLF2	ENST00000592003.1	c.75+453T>C		intron_variant	Intron 1 of 1	3		ENSP00000465035.1

Frequencies

GnomAD3 genomes AF: 0.813 AC: 123106 AN: 151358 Hom.: 50954 Cov.: 33

Gnomad AFR AF: 0.949

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.860

Gnomad ASJ AF: 0.816

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.756

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.888

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.817

GnomAD2 exomes AF: 0.751 AC: 33283 AN: 44342 AF XY: 0.746

Gnomad AFR exome AF: 0.944

Gnomad AMR exome AF: 0.888

Gnomad ASJ exome AF: 0.802

Gnomad EAS exome AF: 0.400

Gnomad FIN exome AF: 0.755

Gnomad NFE exome AF: 0.722

Gnomad OTH exome AF: 0.813

GnomAD4 exome AF: 0.754 AC: 945101 AN: 1254192 Hom.: 358559 Cov.: 53 AF XY: 0.753 AC XY: 464857 AN XY: 617010

Gnomad4 AFR exome AF: 0.961 AC: 23632 AN: 24584

Gnomad4 AMR exome AF: 0.884 AC: 14045 AN: 15896

Gnomad4 ASJ exome AF: 0.817 AC: 15731 AN: 19248

Gnomad4 EAS exome AF: 0.479 AC: 13195 AN: 27560

Gnomad4 SAS exome AF: 0.752 AC: 46445 AN: 61754

Gnomad4 FIN exome AF: 0.782 AC: 24212 AN: 30974

Gnomad4 NFE exome AF: 0.752 AC: 766080 AN: 1019140

Gnomad4 Remaining exome AF: 0.754 AC: 38765 AN: 51392

GnomAD4 genome AF: 0.814 AC: 123225 AN: 151468 Hom.: 51016 Cov.: 33 AF XY: 0.814 AC XY: 60208 AN XY: 73996

Gnomad4 AFR AF: 0.949 AC: 0.949016 AN: 0.949016

Gnomad4 AMR AF: 0.860 AC: 0.859703 AN: 0.859703

Gnomad4 ASJ AF: 0.816 AC: 0.81585 AN: 0.81585

Gnomad4 EAS AF: 0.478 AC: 0.477996 AN: 0.477996

Gnomad4 SAS AF: 0.757 AC: 0.756639 AN: 0.756639

Gnomad4 FIN AF: 0.794 AC: 0.79397 AN: 0.79397

Gnomad4 NFE AF: 0.752 AC: 0.752185 AN: 0.752185

Gnomad4 OTH AF: 0.813 AC: 0.813213 AN: 0.813213

Alfa AF: 0.776 Hom.: 17476

Bravo AF: 0.826

TwinsUK AF: 0.760 AC: 2818

ALSPAC AF: 0.749 AC: 2886

ESP6500AA AF: 0.950 AC: 1680

ESP6500EA AF: 0.795 AC: 3452

ExAC AF: 0.665 AC: 51590

Asia WGS AF: 0.631 AC: 2119 AN: 3352

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	17
DANN	Benign	0.68
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	7.1e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	1.2	N
REVEL	Benign	0.092
Sift	Benign	0.21	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.039
MPC		2.2
ClinPred		0.0085	T
GERP RS		0.56
Varity_R		0.079
gMVP		0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Publications

LitVar

Other links and lift over

dbSNP: rs3745318; hg19: chr19-16436262; COSMIC: COSV50179778; COSMIC: COSV50179778;