2-169735203-G-T

Variant names:

• chr2-169735203-G-T
• rs1688480972
• NM_144711.6:c.189G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_144711.6(KLHL23):​c.189G>T​(p.Lys63Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,192 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KLHL23 NM_144711.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53

Genes affected

KLHL23 (HGNC:27506): (kelch like family member 23)

PHOSPHO2-KLHL23 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL23	NM_144711.6	c.189G>T	p.Lys63Asn	missense_variant	Exon 2 of 4	ENST00000392647.7	NP_653312.2
PHOSPHO2-KLHL23	NM_001199290.3	c.189G>T	p.Lys63Asn	missense_variant	Exon 4 of 6		NP_001186219.1
PHOSPHO2-KLHL23	NR_144936.2	n.359-6182G>T		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL23	ENST00000392647.7	c.189G>T	p.Lys63Asn	missense_variant	Exon 2 of 4	1	NM_144711.6	ENSP00000376419.2
KLHL23	ENST00000272797.8	c.189G>T	p.Lys63Asn	missense_variant	Exon 4 of 6	2		ENSP00000272797.4
KLHL23	ENST00000602521.1	c.-266-6182G>T		intron_variant	Intron 1 of 2	3		ENSP00000475081.1
KLHL23	ENST00000498202.6	c.-266-6182G>T		intron_variant	Intron 4 of 5	3		ENSP00000474581.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456192 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723988

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.189G>T (p.K63N) alteration is located in exon 2 (coding exon 1) of the KLHL23 gene. This alteration results from a G to T substitution at nucleotide position 189, causing the lysine (K) at amino acid position 63 to be replaced by an asparagine (N). 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	0.87
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T
Eigen	Benign	0.072
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	.;T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.055	T;T
Polyphen		0.20	B;B
Vest4		0.60
MutPred		0.68		Loss of methylation at K63 (P = 0.0023);Loss of methylation at K63 (P = 0.0023);
MVP		0.71
MPC		0.48
ClinPred		0.89	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs1688480972; hg19: chr2-170591713;