NM_017658.5:c.782A>G

Variant names:

• chr14-44945147-T-C
• NM_017658.5:c.782A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017658.5(KLHL28):​c.782A>G​(p.His261Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL28 NM_017658.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.62

Genes affected

KLHL28 (HGNC:19741): (kelch like family member 28)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL28	NM_017658.5	c.782A>G	p.His261Arg	missense_variant	Exon 2 of 5	ENST00000396128.9	NP_060128.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL28	ENST00000396128.9	c.782A>G	p.His261Arg	missense_variant	Exon 2 of 5	1	NM_017658.5	ENSP00000379434.4
KLHL28	ENST00000355081.3	c.824A>G	p.His275Arg	missense_variant	Exon 2 of 5	1		ENSP00000347193.2
KLHL28	ENST00000579157.1	c.*86A>G		downstream_gene_variant		2		ENSP00000462025.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.782A>G (p.H261R) alteration is located in exon 2 (coding exon 1) of the KLHL28 gene. This alteration results from a A to G substitution at nucleotide position 782, causing the histidine (H) at amino acid position 261 to be replaced by an arginine (R). 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	0.79
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	-0.040	T
MutationAssessor	Pathogenic	3.5	M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.67
Sift	Benign	0.089	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.053	B;.
Vest4		0.86
MutPred		0.49		Gain of catalytic residue at P264 (P = 0.0135);.;
MVP		0.83
MPC		1.0
ClinPred		0.91	D
GERP RS		5.6
Varity_R		0.59
gMVP		0.86

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: chr14-45414350;