rs147294651

chr2-169510176-G-Achr2-169510176-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006063.3(KLHL41):c.398G>A(p.Gly133Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,058 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (24 hom.)
• Consequence: KLHL41 NM_006063.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.93

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012224913).
• BP6: Variant 2-169510176-G-A is Benign according to our data. Variant chr2-169510176-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00139 (212/152196) while in subpopulation SAS AF= 0.00872 (42/4816). AF 95% confidence interval is 0.00663. There are 1 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL41	NM_006063.3	c.398G>A	p.Gly133Asp	missense_variant	1/6	ENST00000284669.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL41	ENST00000284669.2	c.398G>A	p.Gly133Asp	missense_variant	1/6	1	NM_006063.3	P1

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152078 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00892

Gnomad FIN AF: 0.000567

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00224 AC: 561 AN: 250590 Hom.: 4 AF XY: 0.00267 AC XY: 362 AN XY: 135768

Gnomad AFR exome AF: 0.0000636

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00810

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.00312

GnomAD4 exome AF: 0.00179 AC: 2617 AN: 1461862 Hom.: 24 Cov.: 32 AF XY: 0.00202 AC XY: 1469 AN XY: 727238

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00837

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00135

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152196 Hom.: 1 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74390

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00872

Gnomad4 FIN AF: 0.000567

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00193 Hom.: 1

Bravo AF: 0.00118

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00220 AC: 267

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	KLHL41: BS2 -

KLHL41-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nemaline myopathy 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	25
Dann	Benign	0.97
DEOGEN2	Benign	0.031	T
Eigen	Benign	0.040
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.12	N
MutationTaster	Benign	0.86	D;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.11
Sift	Benign	0.33	T
Sift4G	Uncertain	0.049	D
Polyphen		0.57	P
Vest4		0.54
MVP		0.77
MPC		0.52
ClinPred		0.023	T
GERP RS		4.3
Varity_R		0.13
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147294651; hg19: chr2-170366686;