rs139415849

Positions:

• chr2-169510641-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 8.02

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]

ACMG classification

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/exons	MANE	UniProt
KLHL41	NM_006063.3	c.863T>G	p.Leu288Arg	missense_variant	1/6	ENST00000284669.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL41	ENST00000284669.2	c.863T>G	p.Leu288Arg	missense_variant	1/6	1	NM_006063.3	P1

Frequencies

GnomAD3 genomes AF: 0.00568 AC: 864 AN: 152170 Hom.: 1 Cov.: 32

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.: 10 AF XY: 0.00554 AC XY: 753 AN XY: 135912

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.: 92 Cov.: 33 AF XY: 0.00765 AC XY: 5563 AN XY: 727244

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.: 1 Cov.: 32 AF XY: 0.00561 AC XY: 418 AN XY: 74482

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.: 17

Bravo AF: 0.00479

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.00849 AC: 73

ExAC AF: 0.00540 AC: 656

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00763

EpiControl AF: 0.00688

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	KLHL41: BS2 -

Nemaline myopathy 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
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	T
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.016	D
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.93
MPC		1.2
ClinPred		0.0080	T
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

Other links and lift over

dbSNP: rs139415849; hg19: chr2-170367151;