rs116420871

Variant names:

• chr17-41842275-A-C
• rs116420871
• NM_152467.5:c.647A>C
• KLHL10 p.Gln216Pro

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_152467.5(KLHL10):​c.647A>C​(p.Gln216Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000663 in 1,614,166 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (6 hom.)
• Consequence: KLHL10 NM_152467.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:3
• Conservation: PhyloP100: 0.528
• Publications: 5 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005472094).
• BP6: Variant 17-41842275-A-C is Benign according to our data. Variant chr17-41842275-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 40008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 527 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152467.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL10	NM_152467.5	MANE Select	c.647A>C	p.Gln216Pro	missense	Exon 2 of 5	NP_689680.2	A0A140VJM8
	KLHL10	NM_001329595.1		c.647A>C	p.Gln216Pro	missense	Exon 4 of 7	NP_001316524.1	A0A140VJM8
	KLHL10	NM_001329596.2		c.383A>C	p.Gln128Pro	missense	Exon 2 of 5	NP_001316525.1	B4DX37

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL10	ENST00000293303.5	TSL:1 MANE Select	c.647A>C	p.Gln216Pro	missense	Exon 2 of 5	ENSP00000293303.4	Q6JEL2
	KLHL10	ENST00000859834.1		c.647A>C	p.Gln216Pro	missense	Exon 4 of 7	ENSP00000529893.1
	KLHL10	ENST00000913027.1		c.647A>C	p.Gln216Pro	missense	Exon 4 of 7	ENSP00000583086.1

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 528 AN: 152214 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

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: 0.0000441

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000980 AC: 244 AN: 249080 AF XY: 0.000614

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000371 AC: 543 AN: 1461834 Hom.: 6 Cov.: 35 AF XY: 0.000322 AC XY: 234 AN XY: 727226

African (AFR) AF: 0.0127 AC: 425 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1112004

Other (OTH) AF: 0.000762 AC: 46 AN: 60396

GnomAD4 genome AF: 0.00346 AC: 527 AN: 152332 Hom.: 6 Cov.: 31 AF XY: 0.00313 AC XY: 233 AN XY: 74488

African (AFR) AF: 0.0121 AC: 505 AN: 41574

American (AMR) AF: 0.000785 AC: 12 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00121 Hom.: 2

Bravo AF: 0.00388

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	1	1	Spermatogenic failure 11 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.64	N
PhyloP100		0.53
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Benign	0.27	T
Sift4G	Benign	0.27	T
Varity_R		0.42
gMVP		0.59
Mutation Taster		=81/19	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs116420871;

hg19: chr17-39998527;