17-41842050-G-C

Variant names:

• chr17-41842050-G-C
• NM_152467.5:c.422G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152467.5(KLHL10):​c.422G>C​(p.Cys141Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLHL10 NM_152467.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.72
• Publications: 0 publications found

Genes affected

KLHL10 (HGNC:18829): (kelch like family member 10) The protein encoded by this gene belongs to the kelch repeat-containing family, and contains an N-terminal BTB/POZ domain a BACK domain and six C-terminal kelch repeats. Kelch domains are thought to form a four stranded beta-sheet blade structure that can fold into a beta-propeller domain when multiple kelch repeats are found together. Mutations in this gene have been associated with oligozoospermia in some infertile males. [provided by RefSeq, Jul 2016]

KLHL10 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• spermatogenic failure 11

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL10	NM_152467.5	c.422G>C	p.Cys141Ser	missense_variant	Exon 2 of 5	ENST00000293303.5	NP_689680.2
KLHL10	NM_001329595.1	c.422G>C	p.Cys141Ser	missense_variant	Exon 4 of 7		NP_001316524.1
KLHL10	NM_001329596.2	c.158G>C	p.Cys53Ser	missense_variant	Exon 2 of 5		NP_001316525.1
KLHL10	XM_047435897.1	c.422G>C	p.Cys141Ser	missense_variant	Exon 3 of 6		XP_047291853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL10	ENST00000293303.5	c.422G>C	p.Cys141Ser	missense_variant	Exon 2 of 5	1	NM_152467.5	ENSP00000293303.4
KLHL10	ENST00000438813.1	c.404G>C	p.Cys135Ser	missense_variant	Exon 2 of 2	4		ENSP00000416221.1
KLHL10	ENST00000485613.1	n.468G>C		non_coding_transcript_exon_variant	Exon 2 of 2	4
KLHL10	ENST00000448203.2	c.*56G>C		downstream_gene_variant		4		ENSP00000391983.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.422G>C (p.C141S) alteration is located in exon 2 (coding exon 2) of the KLHL10 gene. This alteration results from a G to C substitution at nucleotide position 422, causing the cysteine (C) at amino acid position 141 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.5	M;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-9.5	D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0080	D;T
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.76		Loss of stability (P = 0.0518);.;
MVP		0.87
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.85
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr17-39998302;