Genetic Variant KLHL32:p.Val251Val (chr6-97113908-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001323256.2(KLHL32):c.832C>T(p.Pro278Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0064 in 1,614,062 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0070 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 95 hom. )

Consequence

KLHL32
NM_001323256.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0150

Variant links:

Genes affected

KLHL32 (HGNC:21221): (kelch like family member 32)

KLHL32 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00380975).

BP6

Variant 6-97113908-C-T is Benign according to our data. Variant chr6-97113908-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2656778.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL32	NM_052904.4 link	c.753C>T	p.Val251Val	synonymous_variant	Exon 7 of 11	ENST00000369261.9	NP_443136.2	Q96NJ5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL32	ENST00000369261.9 link	c.753C>T	p.Val251Val	synonymous_variant	Exon 7 of 11	2	NM_052904.4	ENSP00000358265.4		Q96NJ5-1

Frequencies

GnomAD3 genomes

AF:

0.00700

AC:

1065

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0558

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00587

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00778

AC:

1955

AN:

251378

Hom.:

AF XY:

0.00768

AC XY:

1044

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.0510

Gnomad NFE exome

AF:

0.00640

Gnomad OTH exome

AF:

0.00848

GnomAD4 exome

AF:

0.00634

AC:

9263

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00612

AC XY:

4448

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000974

Gnomad4 FIN exome

AF:

0.0471

Gnomad4 NFE exome

AF:

0.00560

Gnomad4 OTH exome

AF:

0.00621

GnomAD4 genome

AF:

0.00700

AC:

1065

AN:

152180

Hom.:

Cov.:

AF XY:

0.00864

AC XY:

643

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.0558

Gnomad4 NFE

AF:

0.00587

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00511

Hom.:

Bravo

AF:

0.00290

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00731

AC:

888

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00403

EpiControl

AF:

0.00474

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KLHL32: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

1.7

DANN

Benign

0.62

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.1

PROVEAN

Benign

0.68

REVEL

Benign

0.017

Sift

Pathogenic

0.0

MVP

0.36

ClinPred

0.032

GERP RS

1.2

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