dbSNP rs1039574984: KLHL26:p.Asn27Lys (chr19-18637135-C-G) – 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.81C>G(p.Asn27Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KLHL26
NM_018316.3 missense, splice_region

Scores

Splicing: ADA: 0.008610

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.373

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=0.08468157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL26	NM_018316.3 link	c.81C>G	p.Asn27Lys	missense_variant, splice_region_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.81C>G	p.Asn27Lys	missense_variant, splice_region_variant	Exon 1 of 3	1	NM_018316.3	ENSP00000300976.3		Q53HC5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1187900

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

573260

African (AFR)

AF:

0.00

AC:

AN:

23616

American (AMR)

AF:

0.00

AC:

AN:

9738

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16588

East Asian (EAS)

AF:

0.00

AC:

AN:

27026

South Asian (SAS)

AF:

0.00

AC:

AN:

45744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4568

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

978878

Other (OTH)

AF:

0.00

AC:

AN:

48526

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

Feb 28, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.81C>G (p.N27K) alteration is located in exon 1 (coding exon 1) of the KLHL26 gene. This alteration results from a C to G substitution at nucleotide position 81, causing the asparagine (N) at amino acid position 27 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

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.024

T;T;T

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.36

T;T;T

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.085

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.

PhyloP100

0.37

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.48

N;.;.

REVEL

Benign

0.14

Sift

Benign

0.23

T;.;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0050

B;.;.

Vest4

0.077

MutPred

0.23

Gain of ubiquitination at N27 (P = 0.0045);Gain of ubiquitination at N27 (P = 0.0045);Gain of ubiquitination at N27 (P = 0.0045);

MVP

0.72

MPC

0.67

ClinPred

0.16

GERP RS

2.7

PromoterAI

0.12

Neutral

(source)

Varity_R

0.11

gMVP

0.11

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0086

dbscSNV1_RF

Benign

0.15

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over