Genetic Variant KLF16:p.Arg219Cys (chr19-1854563-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_031918.4(KLF16):c.655C>T(p.Arg219Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000635 in 1,575,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

KLF16
NM_031918.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63

Variant links:

Genes affected

KLF16 (HGNC:16857): (KLF transcription factor 16) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within dopamine receptor signaling pathway. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

KLF16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31672043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLF16	NM_031918.4 link	c.655C>T	p.Arg219Cys	missense_variant	Exon 2 of 2	ENST00000250916.6	NP_114124.1	Q9BXK1
KLF16	XM_047439498.1 link	c.625C>T	p.Arg209Cys	missense_variant	Exon 2 of 2		XP_047295454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLF16	ENST00000250916.6 link	c.655C>T	p.Arg219Cys	missense_variant	Exon 2 of 2	1	NM_031918.4	ENSP00000250916.3	Q9BXK1
KLF16	ENST00000617223.1 link	c.655C>T	p.Arg219Cys	missense_variant	Exon 2 of 3	1		ENSP00000483701.1	Q9BXK1
KLF16	ENST00000541015.5 link	n.655C>T		non_coding_transcript_exon_variant	Exon 2 of 3	1		ENSP00000439973.1	Q9BXK1
KLF16	ENST00000592313.1 link	c.244C>T	p.Arg82Cys	missense_variant	Exon 2 of 2	3		ENSP00000480570.1	A0A087WWX5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000632

AC:

AN:

1423160

Hom.:

Cov.:

AF XY:

0.00000566

AC XY:

AN XY:

706934

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000238

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000636

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.655C>T (p.R219C) alteration is located in exon 2 (coding exon 2) of the KLF16 gene. This alteration results from a C to T substitution at nucleotide position 655, causing the arginine (R) at amino acid position 219 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.024

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.82

.;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.9

D;.;.

REVEL

Benign

0.067

Sift

Uncertain

0.014

D;.;.

Sift4G

Uncertain

0.013

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.33

MutPred

0.27

Loss of MoRF binding (P = 0.0321);Loss of MoRF binding (P = 0.0321);.;

MVP

0.36

MPC

2.9

ClinPred

0.91

GERP RS

3.3

Varity_R

0.18

gMVP

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over