2-169510430-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006063.3(KLHL41):​c.652G>C​(p.Val218Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V218M) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

KLHL41
NM_006063.3 missense

Scores

3
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.45
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18230581).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KLHL41NM_006063.3 linkc.652G>C p.Val218Leu 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
KLHL41ENST00000284669.2 linkc.652G>C p.Val218Leu missense_variant Exon 1 of 6 1 NM_006063.3 ENSP00000284669.1 O60662-1
ENSG00000251569ENST00000513963.1 linkc.925-4144G>C intron_variant Intron 11 of 15 2 ENSP00000424363.1 E9PBE3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461784
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727186
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.067
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
20
DANN
Benign
0.87
DEOGEN2
Benign
0.060
T
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.14
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.88
D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
-1.0
N
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.38
N
REVEL
Benign
0.11
Sift
Benign
0.52
T
Sift4G
Benign
0.69
T
Polyphen
0.0030
B
Vest4
0.41
MutPred
0.47
Loss of helix (P = 0.079);
MVP
0.54
MPC
0.30
ClinPred
0.47
T
GERP RS
4.9
Varity_R
0.13
gMVP
0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-170366940; API