rs34623017

Positions:

• chr2-169518254-A-G

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.1441A>G​(p.Met481Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,100 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (15 hom.)
• Consequence: KLHL41 NM_006063.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 9.32

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]

ENSG00000251569 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00918287).
• BP6: Variant 2-169518254-A-G is Benign according to our data. Variant chr2-169518254-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00637 (970/152336) while in subpopulation AFR AF= 0.0219 (912/41582). AF 95% confidence interval is 0.0208. There are 16 homozygotes in gnomad4. There are 433 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL41	NM_006063.3	c.1441A>G	p.Met481Val	missense_variant	4/6	ENST00000284669.2	NP_006054.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL41	ENST00000284669.2	c.1441A>G	p.Met481Val	missense_variant	4/6	1	NM_006063.3	ENSP00000284669.1
ENSG00000251569	ENST00000513963.1	c.1255A>G	p.Met419Val	missense_variant	14/16	2		ENSP00000424363.1
KLHL41	ENST00000463400.1	n.445A>G		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes AF: 0.00636 AC: 968 AN: 152218 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00170 AC: 427 AN: 251260 Hom.: 5 AF XY: 0.00118 AC XY: 160 AN XY: 135788

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000702 AC: 1026 AN: 1461764 Hom.: 15 Cov.: 31 AF XY: 0.000587 AC XY: 427 AN XY: 727192

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00637 AC: 970 AN: 152336 Hom.: 16 Cov.: 32 AF XY: 0.00581 AC XY: 433 AN XY: 74488

Gnomad4 AFR AF: 0.0219

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00112 Hom.: 3

Bravo AF: 0.00790

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0220 AC: 97

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00207 AC: 251

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Nemaline myopathy 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Benign	0.0092	T;T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.6	.;H
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.81	N;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.96	.;D
Vest4		0.84
MVP		0.95
MPC		0.62
ClinPred		0.090	T
GERP RS		5.8
Varity_R		0.67
gMVP		0.83

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: rs34623017; hg19: chr2-170374764; COSMIC: COSV99034452; COSMIC: COSV99034452;