NM_006063.3:c.1562A>C

Variant names:

• chr2-169518375-A-C
• NM_006063.3:c.1562A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006063.3(KLHL41):​c.1562A>C​(p.Lys521Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KLHL41 NM_006063.3 missense, splice_region
• Scores: Splicing: ADA: 0.03837
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL41	NM_006063.3	c.1562A>C	p.Lys521Thr	missense_variant, splice_region_variant	Exon 4 of 6	ENST00000284669.2	NP_006054.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL41	ENST00000284669.2	c.1562A>C	p.Lys521Thr	missense_variant, splice_region_variant	Exon 4 of 6	1	NM_006063.3	ENSP00000284669.1
ENSG00000251569	ENST00000513963.1	c.1376A>C	p.Lys459Thr	missense_variant, splice_region_variant	Exon 14 of 16	2		ENSP00000424363.1
KLHL41	ENST00000463400.1	n.566A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453710 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723256

Gnomad4 AFR exome AF: 0.00

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: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.4	.;L
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.2	N;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.96	.;D
Vest4		0.78
MutPred		0.49		.;Loss of ubiquitination at K521 (P = 0.0297);
MVP		0.77
MPC		1.1
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.40
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.038
dbscSNV1_RF	Benign	0.27
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: chr2-170374885;