2-169735741-A-G

Position:

• chr2-169735741-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000392647.7(KLHL23):​c.727A>G​(p.Arg243Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 32)
• Consequence: KLHL23 ENST00000392647.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.32

Genes affected

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

PHOSPHO2-KLHL23 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26515782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL23	NM_144711.6	c.727A>G	p.Arg243Gly	missense_variant	2/4	ENST00000392647.7	NP_653312.2
PHOSPHO2-KLHL23	NR_144936.2	n.359-5644A>G		intron_variant, non_coding_transcript_variant
PHOSPHO2-KLHL23	NM_001199290.3	c.727A>G	p.Arg243Gly	missense_variant	4/6		NP_001186219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL23	ENST00000392647.7	c.727A>G	p.Arg243Gly	missense_variant	2/4	1	NM_144711.6	ENSP00000376419	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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 20, 2023

The c.727A>G (p.R243G) alteration is located in exon 2 (coding exon 1) of the KLHL23 gene. This alteration results from a A to G substitution at nucleotide position 727, causing the arginine (R) at amino acid position 243 to be replaced by a glycine (G). 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	0.16
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.0	N;N;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.066	T;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.20
MutPred		0.63		Loss of catalytic residue at R243 (P = 0.0561);Loss of catalytic residue at R243 (P = 0.0561);.;
MVP		0.77
MPC		0.13
ClinPred		0.57	D
GERP RS		5.8
Varity_R		0.22
gMVP		0.52

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: chr2-170592251;