Genetic Variant KLHL20:p.Met236Ile (chr1-173751874-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014458.4(KLHL20):c.708G>T(p.Met236Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

KLHL20
NM_014458.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.56

Publications

0 publications found

Variant links:

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]

KLHL20 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: G2P

KLHL20 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.047664046).

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL20	NM_014458.4 link	c.708G>T	p.Met236Ile	missense_variant	Exon 4 of 12	ENST00000209884.5	NP_055273.2	Q9Y2M5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL20	ENST00000209884.5 link	c.708G>T	p.Met236Ile	missense_variant	Exon 4 of 12	1	NM_014458.4	ENSP00000209884.4		Q9Y2M5-1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000797

AC:

AN:

251058

AF XY:

0.0000516

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

33478

American (AMR)

AF:

0.000134

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111972

Other (OTH)

AF:

0.0000662

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000276

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41552

American (AMR)

AF:

0.000327

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000964

Hom.:

Bravo

AF:

0.000332

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.708G>T (p.M236I) alteration is located in exon 4 (coding exon 3) of the KLHL20 gene. This alteration results from a G to T substitution at nucleotide position 708, causing the methionine (M) at amino acid position 236 to be replaced by an isoleucine (I). 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

0.61

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.076

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.011

MetaRNN

Benign

0.048

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.94

PhyloP100

7.6

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.36

Sift

Benign

1.0

Sift4G

Benign

0.77

Polyphen

0.0030

Vest4

0.58

MutPred

0.60

Gain of helix (P = 0.0696);

MVP

0.52

MPC

0.94

ClinPred

0.065

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.73

Mutation Taster

=57/43

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr1-173751874-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over