rs201856772

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_152393.4(KLHL40):c.1762G>A(p.Glu588Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00047 in 1,598,414 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00035 ( 2 hom. )

Consequence

KLHL40
NM_152393.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 6.41

Publications

3 publications found

Variant links:

Genes affected

KLHL40 (HGNC:30372): (kelch like family member 40) This gene encodes a protein containing a BACK domain, a BTB/POZ domain, and 5 Kelch repeats, however, its exact function is not known. The gene and the multi-domain protein structure are conserved across different taxa, including primates, rodents, chicken and zebrafish. [provided by RefSeq, Dec 2012]

KLHL40 Gene-Disease associations (from GenCC):

nemaline myopathy 8
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
severe congenital nemaline myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KLHL40 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035648078).

BP6

Variant 3-42691889-G-A is Benign according to our data. Variant chr3-42691889-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474333.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00165 (244/147654) while in subpopulation AFR AF = 0.00531 (198/37258). AF 95% confidence interval is 0.00471. There are 0 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL40	NM_152393.4 link	c.1762G>A	p.Glu588Lys	missense_variant	Exon 6 of 6	ENST00000287777.5	NP_689606.2	Q2TBA0-1A8K5H9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL40	ENST00000287777.5 link	c.1762G>A	p.Glu588Lys	missense_variant	Exon 6 of 6	1	NM_152393.4	ENSP00000287777.4		Q2TBA0-1

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

245

AN:

147540

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00533

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00113

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000990

GnomAD2 exomes

AF:

0.000663

AC:

166

AN:

250232

AF XY:

0.000576

show subpopulations

Gnomad AFR exome

AF:

0.00511

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00158

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000284

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000349

AC:

507

AN:

1450760

Hom.:

Cov.:

AF XY:

0.000332

AC XY:

240

AN XY:

722738

show subpopulations

African (AFR)

AF:

0.00453

AC:

135

AN:

29804

American (AMR)

AF:

0.000767

AC:

AN:

44352

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00111

AC:

AN:

39662

South Asian (SAS)

AF:

0.000186

AC:

AN:

86094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00245

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.000203

AC:

225

AN:

1105928

Other (OTH)

AF:

0.000653

AC:

AN:

59718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00165

AC:

244

AN:

147654

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

124

AN XY:

72266

show subpopulations

African (AFR)

AF:

0.00531

AC:

198

AN:

37258

American (AMR)

AF:

0.00113

AC:

AN:

15090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00116

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000280

AC:

AN:

67972

Other (OTH)

AF:

0.000979

AC:

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000799

Hom.:

Bravo

AF:

0.00194

ExAC

AF:

0.000816

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nemaline myopathy 8

Uncertain:2Benign:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Oct 13, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant (GRCh38; NM_152393.4:c.1762G>A:p.Glu588Lys) results in a missense mutation with the conversion of Glutamate (Acidic amino acid) to Lysine (Basic amino acid) in the KLHL40 protein. This variant has a strong Conservation score. Multiple lines of computational evidence support a deleterious effect on the gene or gene product for this variant. Reputable source recently reports variant as benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant is associated with the following publications: PubMed: 20301465, 23746549, 27528495, 26754003, 27762439. Based on conflicting evidence or insufficient data to determine whether the variant is benign or pathogenic, the clinical significance of this alteration remains unclear. In summary, this variant meets our criteria for classification as of Unknown Clinical Significance based on the evidence outlined. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Dec 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.036

MetaSVM

Uncertain

0.18

MutationAssessor

Uncertain

2.4

PhyloP100

6.4

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.59

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.026

Polyphen

0.99

Vest4

0.82

MVP

0.86

MPC

0.30

ClinPred

0.023

GERP RS

3.3

Varity_R

0.40

gMVP

0.64

Mutation Taster

=25/75

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over