dbSNP rs2232463: KLHL21:p.Gly534Asp (chr1-6595384-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000377663.3(KLHL21):c.1601G>A(p.Gly534Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0247 in 1,048,350 control chromosomes in the GnomAD database, including 425 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.021 ( 64 hom., cov: 33)

Exomes 𝑓: 0.025 ( 361 hom. )

Consequence

KLHL21
ENST00000377663.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.35

Variant links:

Genes affected

KLHL21 (HGNC:29041): (kelch like family member 21) Enables cullin family protein binding activity. Contributes to ubiquitin-protein transferase activity. Involved in chromosome passenger complex localization to spindle midzone; protein ubiquitination; and regulation of cytokinesis. Located in polar microtubule. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

KLHL21 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002902478).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0214 (3262/152308) while in subpopulation NFE AF= 0.0333 (2262/68016). AF 95% confidence interval is 0.0321. There are 64 homozygotes in gnomad4. There are 1494 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 64 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL21	NM_014851.4 link	c.1500+101G>A		intron_variant	Intron 3 of 3	ENST00000377658.8	NP_055666.2	Q9UJP4-1
KLHL21	NM_001324309.2 link	c.1500+101G>A		intron_variant	Intron 3 of 3		NP_001311238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL21	ENST00000377658.8 link	c.1500+101G>A		intron_variant	Intron 3 of 3	1	NM_014851.4	ENSP00000366886.4		Q9UJP4-1

Frequencies

GnomAD3 genomes

AF:

0.0214

AC:

3262

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00610

Gnomad AMI

AF:

0.0921

Gnomad AMR

AF:

0.0233

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.0210

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0333

Gnomad OTH

AF:

0.0201

GnomAD3 exomes

AF:

0.0201

AC:

3751

AN:

186952

Hom.:

AF XY:

0.0198

AC XY:

1981

AN XY:

100024

show subpopulations

Gnomad AFR exome

AF:

0.00549

Gnomad AMR exome

AF:

0.0190

Gnomad ASJ exome

AF:

0.00625

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00301

Gnomad FIN exome

AF:

0.0253

Gnomad NFE exome

AF:

0.0319

Gnomad OTH exome

AF:

0.0211

GnomAD4 exome

AF:

0.0252

AC:

22604

AN:

896042

Hom.:

361

Cov.:

AF XY:

0.0245

AC XY:

11380

AN XY:

464148

show subpopulations

Gnomad4 AFR exome

AF:

0.00533

Gnomad4 AMR exome

AF:

0.0186

Gnomad4 ASJ exome

AF:

0.00601

Gnomad4 EAS exome

AF:

0.0000286

Gnomad4 SAS exome

AF:

0.00371

Gnomad4 FIN exome

AF:

0.0254

Gnomad4 NFE exome

AF:

0.0314

Gnomad4 OTH exome

AF:

0.0221

GnomAD4 genome

AF:

0.0214

AC:

3262

AN:

152308

Hom.:

Cov.:

AF XY:

0.0201

AC XY:

1494

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00609

Gnomad4 AMR

AF:

0.0233

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.0210

Gnomad4 NFE

AF:

0.0333

Gnomad4 OTH

AF:

0.0198

Alfa

AF:

0.0272

Hom.:

Bravo

AF:

0.0201

TwinsUK

AF:

0.0364

AC:

135

ALSPAC

AF:

0.0327

AC:

126

ExAC

AF:

0.0167

AC:

2009

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.97

Eigen

Benign

-0.080

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0029

MetaSVM

Uncertain

-0.25

PROVEAN

Benign

-0.020

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

Polyphen

1.0

Vest4

0.12

ClinPred

0.044

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over