chr4-165238819-G-A

Position:

• chr4-165238819-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_007246.4(KLHL2):​c.301G>A​(p.Glu101Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: KLHL2 NM_007246.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.75

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL2	NM_007246.4	c.301G>A	p.Glu101Lys	missense_variant	4/15	ENST00000226725.11	NP_009177.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL2	ENST00000226725.11	c.301G>A	p.Glu101Lys	missense_variant	4/15	1	NM_007246.4	ENSP00000226725.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727190

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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 30, 2024

The c.313G>A (p.E105K) alteration is located in exon 4 (coding exon 4) of the KLHL2 gene. This alteration results from a G to A substitution at nucleotide position 313, causing the glutamic acid (E) at amino acid position 105 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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;.;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.9	L;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.7	N;D;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.052	T;T;D;T;T
Sift4G	Benign	0.14	T;D;T;T;T
Polyphen		0.87	P;.;.;.;.
Vest4		0.62
MutPred		0.68		Gain of methylation at E101 (P = 0.0271);.;.;.;.;
MVP		0.61
MPC		2.1
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.26
gMVP		0.87

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

LitVar

Other links and lift over

dbSNP: rs1217782197; hg19: chr4-166159971;