chr2-169510641-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_006063.3(KLHL41):c.863T>G(p.Leu288Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00767 in 1,614,174 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 92 hom. )

Consequence

KLHL41
NM_006063.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 8.02

Variant links:

Genes affected

KLHL41 (HGNC:16905): (kelch like family member 41) This gene is a member of the kelch-like family. The encoded protein contains a BACK domain, a BTB/POZ domain, and 5 Kelch repeats. This protein is thought to function in skeletal muscle development and maintenance. Mutations in this gene have been associated with nemaline myopathy (NM), a rare congenital muscle disorder. [provided by RefSeq, Mar 2015]

KLHL41 links:

ENSG00000251569 (HGNC:):

ENSG00000251569 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.012883812).

BP6

Variant 2-169510641-T-G is Benign according to our data. Variant chr2-169510641-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 259912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169510641-T-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00567 (864/152288) while in subpopulation NFE AF= 0.00841 (572/68014). AF 95% confidence interval is 0.00784. There are 1 homozygotes in gnomad4. There are 418 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 92 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL41	NM_006063.3 link	c.863T>G	p.Leu288Arg	missense_variant	Exon 1 of 6	ENST00000284669.2	NP_006054.2	O60662-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL41	ENST00000284669.2 link	c.863T>G	p.Leu288Arg	missense_variant	Exon 1 of 6	1	NM_006063.3	ENSP00000284669.1		O60662-1
ENSG00000251569	ENST00000513963.1 link	c.925-3933T>G		intron_variant	Intron 11 of 15	2		ENSP00000424363.1		E9PBE3

Frequencies

GnomAD3 genomes

AF:

0.00568

AC:

864

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0134

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00841

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00556

AC:

1398

AN:

251464

Hom.:

AF XY:

0.00554

AC XY:

753

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00245

Gnomad FIN exome

AF:

0.0104

Gnomad NFE exome

AF:

0.00843

Gnomad OTH exome

AF:

0.00456

GnomAD4 exome

AF:

0.00787

AC:

11512

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00765

AC XY:

5563

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.00183

Gnomad4 ASJ exome

AF:

0.000650

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00226

Gnomad4 FIN exome

AF:

0.0103

Gnomad4 NFE exome

AF:

0.00927

Gnomad4 OTH exome

AF:

0.00512

GnomAD4 genome

AF:

0.00567

AC:

864

AN:

152288

Hom.:

Cov.:

AF XY:

0.00561

AC XY:

418

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.00274

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0134

Gnomad4 NFE

AF:

0.00841

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00717

Hom.:

Bravo

AF:

0.00479

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00849

AC:

ExAC

AF:

0.00540

AC:

656

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00763

EpiControl

AF:

0.00688

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	KLHL41: BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 03, 2017	- -

Nemaline myopathy 9

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 25, 2020	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.016

MutationAssessor

Uncertain

2.2

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.97

MVP

0.93

MPC

1.2

ClinPred

0.0080

GERP RS

5.3

Varity_R

0.73

gMVP

0.84

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

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