1-6601921-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_014851.4(KLHL21):c.897C>T(p.Asp299=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,562,822 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (27 hom.)
• Consequence: KLHL21 NM_014851.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.131

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 1-6601921-G-A is Benign according to our data. Variant chr1-6601921-G-A is described in ClinVar as [Benign]. Clinvar id is 3034671.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.131 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1782/152352) while in subpopulation AFR AF= 0.0407 (1692/41582). AF 95% confidence interval is 0.0391. There are 31 homozygotes in gnomad4. There are 843 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHL21	NM_014851.4	c.897C>T	p.Asp299=	synonymous_variant	1/4	ENST00000377658.8
KLHL21	NM_001324309.2	c.897C>T	p.Asp299=	synonymous_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHL21	ENST00000377658.8	c.897C>T	p.Asp299=	synonymous_variant	1/4	1	NM_014851.4	P1
KLHL21	ENST00000377663.3	c.897C>T	p.Asp299=	synonymous_variant	1/3	1
KLHL21	ENST00000463043.1	c.-80-2469C>T		intron_variant		5
KLHL21	ENST00000467612.5	c.-80-2469C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1782 AN: 152234 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00297 AC: 504 AN: 169440 Hom.: 9 AF XY: 0.00223 AC XY: 202 AN XY: 90572

Gnomad AFR exome AF: 0.0458

Gnomad AMR exome AF: 0.00195

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00118 AC: 1665 AN: 1410470 Hom.: 27 Cov.: 32 AF XY: 0.00101 AC XY: 703 AN XY: 697086

Gnomad4 AFR exome AF: 0.0423

Gnomad4 AMR exome AF: 0.00249

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000748

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000516

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.0117 AC: 1782 AN: 152352 Hom.: 31 Cov.: 33 AF XY: 0.0113 AC XY: 843 AN XY: 74502

Gnomad4 AFR AF: 0.0407

Gnomad4 AMR AF: 0.00411

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00476 Hom.: 6

Bravo AF: 0.0135

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

KLHL21-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2019

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
BayesDel_noAF	Benign	-0.60
Cadd	Benign	8.2
Dann	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

Other links and lift over

dbSNP: rs2232456; hg19: chr1-6661981;