4-165305681-G-A

Position:

• chr4-165305681-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.995G>A​(p.Arg332Lys) 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. 12/21 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: KLHL2 NM_007246.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.71

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=0.3333398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL2	NM_007246.4	c.995G>A	p.Arg332Lys	missense_variant	9/15	ENST00000226725.11	NP_009177.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL2	ENST00000226725.11	c.995G>A	p.Arg332Lys	missense_variant	9/15	1	NM_007246.4	ENSP00000226725.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Feb 06, 2023

The c.1007G>A (p.R336K) alteration is located in exon 9 (coding exon 9) of the KLHL2 gene. This alteration results from a G to A substitution at nucleotide position 1007, causing the arginine (R) at amino acid position 336 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	Benign	0.10
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T;.;.;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.00099
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.53	N;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.59	N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.42	T;T;T;T;T
Sift4G	Benign	0.49	T;T;T;T;T
Polyphen		0.0020	B;.;.;.;.
Vest4		0.54
MutPred		0.35		Gain of methylation at R332 (P = 0.0227);.;.;.;.;
MVP		0.55
MPC		1.1
ClinPred		0.50	D
GERP RS		6.0
Varity_R		0.42
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: rs1745674714; hg19: chr4-166226833;