Genetic Variant KLHL26:p.Ala2Val (chr19-18637059-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_018316.3(KLHL26):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000822 in 1,217,074 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: not found (cov: 32)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Consequence

KLHL26
NM_018316.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.575

Publications

0 publications found

Variant links:

Genes affected

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

KLHL26 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a modified_residue N-acetylalanine (size 0) in uniprot entity KLH26_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38671315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL26	NM_018316.3 link	c.5C>T	p.Ala2Val	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.5C>T	p.Ala2Val	missense_variant	Exon 1 of 3	1	NM_018316.3	ENSP00000300976.3		Q53HC5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.22e-7

AC:

AN:

1217074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

592786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24214

American (AMR)

AF:

0.00

AC:

AN:

13360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18606

East Asian (EAS)

AF:

0.00

AC:

AN:

27214

South Asian (SAS)

AF:

0.00

AC:

AN:

54170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3816

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

989754

Other (OTH)

AF:

0.00

AC:

AN:

49668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5C>T (p.A2V) alteration is located in exon 1 (coding exon 1) of the KLHL26 gene. This alteration results from a C to T substitution at nucleotide position 5, causing the alanine (A) at amino acid position 2 to be replaced by a valine (V). 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

0.34

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

T;T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.62

T;T;T

M_CAP

Pathogenic

0.71

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

N;.;.

PhyloP100

0.57

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.54

N;.;.

REVEL

Benign

0.28

Sift

Benign

0.047

D;.;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.76

P;.;.

Vest4

0.35

MutPred

0.17

Loss of loop (P = 0.0603);Loss of loop (P = 0.0603);Loss of loop (P = 0.0603);

MVP

0.82

MPC

0.73

ClinPred

0.56

GERP RS

2.5

PromoterAI

-0.71

Under-expression

(source)

Varity_R

0.11

gMVP

0.45

Mutation Taster

=78/22

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

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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