chr4-165299516-G-A

Position:

• chr4-165299516-G-A

Variant summary

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

The NM_007246.4(KLHL2):​c.781G>A​(p.Glu261Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLHL2 NM_007246.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

KLHL2 (HGNC:6353): (kelch like family member 2) Enables actin binding activity and identical protein binding activity. Predicted to be involved in protein ubiquitination. Located in actin cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

KLHL2 (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=0.3909008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL2	NM_007246.4	c.781G>A	p.Glu261Lys	missense_variant	8/15	ENST00000226725.11	NP_009177.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL2	ENST00000226725.11	c.781G>A	p.Glu261Lys	missense_variant	8/15	1	NM_007246.4	ENSP00000226725.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

May 28, 2023

The c.793G>A (p.E265K) alteration is located in exon 8 (coding exon 8) of the KLHL2 gene. This alteration results from a G to A substitution at nucleotide position 793, causing the glutamic acid (E) at amino acid position 265 to be replaced by a lysine (K). 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	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.;.;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	2.0	M;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.32	T;T;T;T;T
Sift4G	Benign	0.46	T;T;T;T;T
Polyphen		0.10	B;.;.;.;.
Vest4		0.67
MutPred		0.36		Gain of ubiquitination at E261 (P = 0.0177);.;.;.;.;
MVP		0.46
MPC		1.4
ClinPred		0.79	D
GERP RS		6.1
Varity_R		0.43
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr4-166220668;