chr1-173751911-C-A

Position:

• chr1-173751911-C-A

Variant summary

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

The NM_014458.4(KLHL20):​c.745C>A​(p.Gln249Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL20 NM_014458.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59

Genes affected

KLHL20 (HGNC:25056): (kelch like family member 20) The protein encoded by this gene is a member of the kelch family of proteins, which is characterized by a 44-56 amino acid repeat motif. The kelch motif appears in many different polypeptide contexts and contains multiple potential protein-protein contact sites. Members of this family are present both throughout the cell and extracellularly, with diverse activities. [provided by RefSeq, Jul 2008]

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/exons	MANE	Protein	UniProt
KLHL20	NM_014458.4	c.745C>A	p.Gln249Lys	missense_variant	4/12	ENST00000209884.5	NP_055273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL20	ENST00000209884.5	c.745C>A	p.Gln249Lys	missense_variant	4/12	1	NM_014458.4	ENSP00000209884.4

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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 09, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.016
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.65	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.27
Sift	Benign	0.079	T
Sift4G	Benign	0.27	T
Polyphen		0.0090	B
Vest4		0.78
MutPred		0.63		Gain of MoRF binding (P = 0.035);
MVP		0.66
MPC		1.1
ClinPred		0.81	D
GERP RS		5.4
Varity_R		0.34
gMVP		0.63

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: chr1-173721050;