13-70107517-C-G

Position:

chr13-70107517-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_020866.3(KLHL1):c.183G>C(p.Glu61Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000438 in 1,612,850 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

KLHL1
NM_020866.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.06

Variant links:

Genes affected

KLHL1 (HGNC:6352): (kelch like family member 1) The KLHL1 protein belongs to a family of actin-organizing proteins related to Drosophila Kelch (Nemes et al., 2000 [PubMed 10888605]).[supplied by OMIM, Feb 2010]

KLHL1 links:

ATXN8OS (HGNC:10561): (ATXN8 opposite strand lncRNA) This gene is an antisense transcript to the KLHL1 gene (homolog to the Drosophila KELCH gene); it does not itself appear to be protein coding. A TAC/TGC trinucleotide repeat expansion that is incorporated into this gene transcript, but not the KLHL1 transcript, causes spinocerebellar ataxia type 8. Presumably the expansion interferes with normal antisense function of this transcript. [provided by RefSeq, Oct 2008]

ATXN8OS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058128834).

BP6

Variant 13-70107517-C-G is Benign according to our data. Variant chr13-70107517-C-G is described in ClinVar as [Benign]. Clinvar id is 3039641.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KLHL1	NM_020866.3 linkuse as main transcript	c.183G>C	p.Glu61Asp	missense_variant	1/11	ENST00000377844.9	NP_065917.1
ATXN8OS	NR_002717.2 linkuse as main transcript	n.305C>G		non_coding_transcript_exon_variant	1/5
KLHL1	NM_001286725.2 linkuse as main transcript	c.183G>C	p.Glu61Asp	missense_variant	1/10		NP_001273654.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KLHL1	ENST00000377844.9 linkuse as main transcript	c.183G>C	p.Glu61Asp	missense_variant	1/11	1	NM_020866.3	ENSP00000367075	P1
KLHL1	ENST00000545028.2 linkuse as main transcript	c.183G>C	p.Glu61Asp	missense_variant	1/10	2		ENSP00000439602
ATXN8OS	ENST00000414504.6 linkuse as main transcript	n.305C>G		non_coding_transcript_exon_variant	1/5	5
ATXN8OS	ENST00000665905.1 linkuse as main transcript	n.189C>G		non_coding_transcript_exon_variant	1/4

Frequencies

GnomAD3 genomes

AF:

0.00224

AC:

341

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.000955

GnomAD3 exomes

AF:

0.000586

AC:

145

AN:

247474

Hom.:

AF XY:

0.000388

AC XY:

AN XY:

133898

show subpopulations

Gnomad AFR exome

AF:

0.00757

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000248

AC:

362

AN:

1460548

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

160

AN XY:

726506

show subpopulations

Gnomad4 AFR exome

AF:

0.00833

Gnomad4 AMR exome

AF:

0.000627

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000763

GnomAD4 genome

AF:

0.00227

AC:

345

AN:

152302

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

161

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00779

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000256

Hom.:

Bravo

AF:

0.00250

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000749

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KLHL1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.10

T;.

Eigen

Benign

-0.074

Eigen_PC

Benign

-0.033

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.0058

T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.48

PROVEAN

Benign

0.15

N;.

REVEL

Benign

0.18

Sift

Benign

0.68

T;.

Sift4G

Benign

0.79

T;T

Polyphen

0.96

P;.

Vest4

0.29

MutPred

0.23

Loss of helix (P = 0.079);Loss of helix (P = 0.079);

MVP

0.78

MPC

0.16

ClinPred

0.040

GERP RS

3.3

Varity_R

0.049

gMVP

0.26

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over