Genetic Variant NM_144711.6:c.158C>T (chr2-169735172-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144711.6(KLHL23):c.158C>T(p.Ala53Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.0000027 ( 0 hom. )

Consequence

KLHL23
NM_144711.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.11

Variant links:

Genes affected

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

KLHL23 links:

PHOSPHO2-KLHL23 (HGNC:):

PHOSPHO2-KLHL23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24816662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL23	NM_144711.6 link	c.158C>T	p.Ala53Val	missense_variant	Exon 2 of 4	ENST00000392647.7	NP_653312.2	Q8NBE8
PHOSPHO2-KLHL23	NM_001199290.3 link	c.158C>T	p.Ala53Val	missense_variant	Exon 4 of 6		NP_001186219.1	Q8NBE8
PHOSPHO2-KLHL23	NR_144936.2 link	n.359-6213C>T		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLHL23	ENST00000392647.7 link	c.158C>T	p.Ala53Val	missense_variant	Exon 2 of 4	1	NM_144711.6	ENSP00000376419.2	Q8NBE8
KLHL23	ENST00000272797.8 link	c.158C>T	p.Ala53Val	missense_variant	Exon 4 of 6	2		ENSP00000272797.4	Q8NBE8
KLHL23	ENST00000602521.1 link	c.-266-6213C>T		intron_variant	Intron 1 of 2	3		ENSP00000475081.1	S4R452
KLHL23	ENST00000498202.6 link	c.-266-6213C>T		intron_variant	Intron 4 of 5	3		ENSP00000474581.1	S4R3P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249342

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134798

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460420

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726380

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.158C>T (p.A53V) alteration is located in exon 2 (coding exon 1) of the KLHL23 gene. This alteration results from a C to T substitution at nucleotide position 158, causing the alanine (A) at amino acid position 53 to be replaced by a valine (V). 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

0.22

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.051

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.77

.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.77

N;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.73

N;N

REVEL

Benign

0.20

Sift

Benign

0.52

T;T

Sift4G

Benign

0.097

T;T

Polyphen

0.0080

B;B

Vest4

0.35

MutPred

0.61

Loss of catalytic residue at A53 (P = 0.0738);Loss of catalytic residue at A53 (P = 0.0738);

MVP

0.75

MPC

0.14

ClinPred

0.28

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over