Genetic Variant NM_018316.3:c.70G>A (chr19-18637124-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018316.3(KLHL26):c.70G>A(p.Glu24Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000998 in 1,202,268 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

KLHL26
NM_018316.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.156

Publications

0 publications found

Variant links:

Genes affected

KLHL26 (HGNC:25623): (kelch like family member 26)

KLHL26 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.14018703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL26	NM_018316.3 link	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 3	ENST00000300976.9	NP_060786.1	Q53HC5A0A024R7N5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL26	ENST00000300976.9 link	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 3	1	NM_018316.3	ENSP00000300976.3		Q53HC5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000998

AC:

AN:

1202268

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

582572

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23824

American (AMR)

AF:

0.00

AC:

AN:

10630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17176

East Asian (EAS)

AF:

0.00

AC:

AN:

27166

South Asian (SAS)

AF:

0.00

AC:

AN:

48552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4438

European-Non Finnish (NFE)

AF:

0.0000101

AC:

AN:

987132

Other (OTH)

AF:

0.0000407

AC:

AN:

49116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.70G>A (p.E24K) alteration is located in exon 1 (coding exon 1) of the KLHL26 gene. This alteration results from a G to A substitution at nucleotide position 70, causing the glutamic acid (E) at amino acid position 24 to be replaced by a lysine (K). 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

0.14

BayesDel_addAF

Benign

0.00040

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.024

T;T;T

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.71

T;T;T

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

N;.;.

PhyloP100

0.16

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.34

N;.;.

REVEL

Benign

0.21

Sift

Benign

0.82

T;.;.

Sift4G

Benign

0.084

T;D;D

Polyphen

0.25

B;.;.

Vest4

0.23

MutPred

0.28

Gain of ubiquitination at E24 (P = 0.0117);Gain of ubiquitination at E24 (P = 0.0117);Gain of ubiquitination at E24 (P = 0.0117);

MVP

0.76

MPC

0.69

ClinPred

0.15

GERP RS

2.7

PromoterAI

-0.025

Neutral

(source)

Varity_R

0.19

gMVP

0.21

Mutation Taster

=81/19

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_018316.3:c.70G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over