chr14-44931534-G-A

Variant names:

• chr14-44931534-G-A
• rs761233044
• NM_017658.5:c.1351C>T

Variant summary

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

The NM_017658.5(KLHL28):​c.1351C>T​(p.Arg451Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000165 in 1,457,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: KLHL28 NM_017658.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.24

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL28	NM_017658.5	c.1351C>T	p.Arg451Cys	missense_variant	Exon 4 of 5	ENST00000396128.9	NP_060128.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL28	ENST00000396128.9	c.1351C>T	p.Arg451Cys	missense_variant	Exon 4 of 5	1	NM_017658.5	ENSP00000379434.4
KLHL28	ENST00000355081.3	c.1393C>T	p.Arg465Cys	missense_variant	Exon 4 of 5	1		ENSP00000347193.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249636 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134996

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1457664 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 725360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000548

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1351C>T (p.R451C) alteration is located in exon 4 (coding exon 3) of the KLHL28 gene. This alteration results from a C to T substitution at nucleotide position 1351, causing the arginine (R) at amino acid position 451 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	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Uncertain	-0.016	T
MutationAssessor	Benign	0.33	N;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.62
Sift	Benign	0.21	T;T
Sift4G	Benign	0.14	T;T
Polyphen		1.0	D;.
Vest4		0.56
MutPred		0.55		Gain of catalytic residue at Y452 (P = 0.0062);.;
MVP		0.84
MPC		1.0
ClinPred		0.85	D
GERP RS		4.7
Varity_R		0.36
gMVP		0.63

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: rs761233044; hg19: chr14-45400737;