Genetic Variant KLHL28:p.Ser223Asn (chr14-44945261-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017658.5(KLHL28):c.668G>A(p.Ser223Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000774 in 1,614,082 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000072 ( 1 hom. )

Consequence

KLHL28
NM_017658.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.82

Variant links:

Genes affected

KLHL28 (HGNC:19741): (kelch like family member 28)

KLHL28 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010680169).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL28	NM_017658.5 link	c.668G>A	p.Ser223Asn	missense_variant	Exon 2 of 5	ENST00000396128.9	NP_060128.2	Q9NXS3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLHL28	ENST00000396128.9 link	c.668G>A	p.Ser223Asn	missense_variant	Exon 2 of 5	1	NM_017658.5	ENSP00000379434.4	Q9NXS3-1
KLHL28	ENST00000355081.3 link	c.710G>A	p.Ser237Asn	missense_variant	Exon 2 of 5	1		ENSP00000347193.2	J3KNY7
KLHL28	ENST00000579157.1 link	c.668G>A	p.Ser223Asn	missense_variant	Exon 3 of 3	2		ENSP00000462025.1	J3KRJ0
KLHL28	ENST00000556500.1 link	c.*180G>A		downstream_gene_variant		4		ENSP00000452061.1	G3V4Y0

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152212

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:

0.00346

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000287

AC:

AN:

251242

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00359

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000718

AC:

105

AN:

1461752

Hom.:

Cov.:

AF XY:

0.0000646

AC XY:

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00204

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000131

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00347

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000140

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.668G>A (p.S223N) alteration is located in exon 2 (coding exon 1) of the KLHL28 gene. This alteration results from a G to A substitution at nucleotide position 668, causing the serine (S) at amino acid position 223 to be replaced by an asparagine (N). 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

Benign

0.15

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

T;.;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.070

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

-0.36

N;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.68

N;N;.

REVEL

Benign

0.087

Sift

Benign

0.32

T;T;.

Sift4G

Benign

0.33

T;T;T

Polyphen

0.011

B;.;.

Vest4

0.37

MVP

0.65

MPC

0.55

ClinPred

0.051

GERP RS

4.8

Varity_R

0.20

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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