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GeneBe

1-6593380-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_014851.4(KLHL21):c.1779C>T(p.Pro593=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000447 in 1,597,940 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0024 ( 3 hom., cov: 33)
Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

KLHL21
NM_014851.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.84
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-6593380-G-A is Benign according to our data. Variant chr1-6593380-G-A is described in ClinVar as [Benign]. Clinvar id is 3035585.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.84 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KLHL21NM_014851.4 linkuse as main transcriptc.1779C>T p.Pro593= synonymous_variant 4/4 ENST00000377658.8
KLHL21NM_001324309.2 linkuse as main transcriptc.*728C>T 3_prime_UTR_variant 4/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KLHL21ENST00000377658.8 linkuse as main transcriptc.1779C>T p.Pro593= synonymous_variant 4/41 NM_014851.4 P1Q9UJP4-1
KLHL21ENST00000377663.3 linkuse as main transcriptc.*1985C>T 3_prime_UTR_variant 3/31 Q9UJP4-2
KLHL21ENST00000467612.5 linkuse as main transcriptc.678C>T p.Pro226= synonymous_variant 4/43
KLHL21ENST00000496707.5 linkuse as main transcript downstream_gene_variant 1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00238
AC:
363
AN:
152208
Hom.:
3
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00830
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000785
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000648
AC:
155
AN:
239278
Hom.:
1
AF XY:
0.000428
AC XY:
56
AN XY:
130708
show subpopulations
Gnomad AFR exome
AF:
0.00888
Gnomad AMR exome
AF:
0.000419
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000333
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000184
Gnomad OTH exome
AF:
0.000341
GnomAD4 exome
AF:
0.000243
AC:
351
AN:
1445614
Hom.:
1
Cov.:
31
AF XY:
0.000237
AC XY:
170
AN XY:
718072
show subpopulations
Gnomad4 AFR exome
AF:
0.00873
Gnomad4 AMR exome
AF:
0.000483
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000815
Gnomad4 OTH exome
AF:
0.000485
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00239
AC:
364
AN:
152326
Hom.:
3
Cov.:
33
AF XY:
0.00230
AC XY:
171
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00830
Gnomad4 AMR
AF:
0.000784
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.0000428
Hom.:
0
Bravo
AF:
0.00266
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

KLHL21-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 06, 2020This 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
BayesDel_noAF
Benign
-0.80
Cadd
Benign
0.17
Dann
Benign
0.89
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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.

Other links and lift over

dbSNP: rs141252990; hg19: chr1-6653440; COSMIC: COSV66553747; COSMIC: COSV66553747; API