2-169510430-G-C

Variant names:

• chr2-169510430-G-C
• NM_006063.3:c.652G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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 𝑓: 0.0000014 (0 hom.)
• Consequence: KLHL41 NM_006063.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.45

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 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
KLHL41	NM_006063.3	c.652G>C	p.Val218Leu	missense_variant	Exon 1 of 6	ENST00000284669.2	NP_006054.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL41	ENST00000284669.2	c.652G>C	p.Val218Leu	missense_variant	Exon 1 of 6	1	NM_006063.3	ENSP00000284669.1
ENSG00000251569	ENST00000513963.1	c.925-4144G>C		intron_variant	Intron 11 of 15	2		ENSP00000424363.1

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

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;