14-44945054-G-C

Position:

• chr14-44945054-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017658.5(KLHL28):​c.875C>G​(p.Ser292Cys) 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: 32)
• Consequence: KLHL28 NM_017658.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.51

Genes affected

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

ACMG classification

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=0.26155385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL28	NM_017658.5	c.875C>G	p.Ser292Cys	missense_variant	2/5	ENST00000396128.9	NP_060128.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL28	ENST00000396128.9	c.875C>G	p.Ser292Cys	missense_variant	2/5	1	NM_017658.5	ENSP00000379434.4
KLHL28	ENST00000355081.3	c.917C>G	p.Ser306Cys	missense_variant	2/5	1		ENSP00000347193.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

May 09, 2023

The c.875C>G (p.S292C) alteration is located in exon 2 (coding exon 1) of the KLHL28 gene. This alteration results from a C to G substitution at nucleotide position 875, causing the serine (S) at amino acid position 292 to be replaced by a cysteine (C). 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	0.20
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.010	T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.68	N;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.91	N;N
REVEL	Benign	0.21
Sift	Benign	0.17	T;T
Sift4G	Benign	0.063	T;D
Polyphen		0.015	B;.
Vest4		0.31
MutPred		0.46		Gain of catalytic residue at K291 (P = 0);.;
MVP		0.77
MPC		0.81
ClinPred		0.60	D
GERP RS		5.8
Varity_R		0.13
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr14-45414257;