2-169514649-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_006063.3(KLHL41):c.1186G>T(p.Val396Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V396G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: KLHL41 NM_006063.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.34

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013213694).
• BP6: Variant 2-169514649-G-T is Benign according to our data. Variant chr2-169514649-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541707.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000565 (86/152186) while in subpopulation AFR AF= 0.0019 (79/41544). AF 95% confidence interval is 0.00156. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL41	NM_006063.3	c.1186G>T	p.Val396Leu	missense_variant	2/6	ENST00000284669.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL41	ENST00000284669.2	c.1186G>T	p.Val396Leu	missense_variant	2/6	1	NM_006063.3	P1
KLHL41	ENST00000463400.1	n.190G>T		non_coding_transcript_exon_variant	2/5	3
KLHL41	ENST00000480330.5	n.159G>T		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251318 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135824

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000595 AC: 87 AN: 1461704 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32 AN XY: 727180

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74400

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000973 Hom.: 0

Bravo AF: 0.000623

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 31, 2020

In silico analysis supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Nemaline myopathy 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.98	D;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.99	N;N
REVEL	Benign	0.13
Sift	Benign	0.10	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.0	.;B
Vest4		0.34
MutPred		0.40		.;Loss of sheet (P = 0.0817);
MVP		0.53
MPC		0.36
ClinPred		0.034	T
GERP RS		5.1
Varity_R		0.12
gMVP		0.19

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: rs147650614; hg19: chr2-170371159;