2-23642431-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_052920.2(KLHL29):c.521C>A(p.Pro174Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000223 in 1,343,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: KLHL29 NM_052920.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.64

Genes affected

KLHL29 (HGNC:29404): (kelch like family member 29)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KLHL29
• BP4: Computational evidence support a benign effect (MetaRNN=0.1454179).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL29	NM_052920.2	c.521C>A	p.Pro174Gln	missense_variant	5/14	ENST00000486442.6
KLHL29	XM_006711929.4	c.521C>A	p.Pro174Gln	missense_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL29	ENST00000486442.6	c.521C>A	p.Pro174Gln	missense_variant	5/14	5	NM_052920.2	P1
KLHL29	ENST00000288548.5	c.41C>A	p.Pro14Gln	missense_variant	1/7	1
KLHL29	ENST00000489446.1	n.602C>A		non_coding_transcript_exon_variant	4/4	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000223 AC: 3 AN: 1343032 Hom.: 0 Cov.: 36 AF XY: 0.00000305 AC XY: 2 AN XY: 654758

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: 0.00000191

Gnomad4 OTH exome AF: 0.0000180

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2022

The c.521C>A (p.P174Q) alteration is located in exon 5 (coding exon 3) of the KLHL29 gene. This alteration results from a C to A substitution at nucleotide position 521, causing the proline (P) at amino acid position 174 to be replaced by a glutamine (Q). 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	Benign	0.073
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	22
Dann	Benign	0.92
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.074
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	0.81	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.30
Sift	Benign	0.31	T
Sift4G	Benign	0.52	T
Vest4		0.18
MutPred		0.69		Gain of sheet (P = 0.0221);
MVP		0.62
ClinPred		0.35	T
GERP RS		5.3
Varity_R		0.078
gMVP		0.31

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: chr2-23865301;