chr1-6595384-C-T

Position:

• chr1-6595384-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35

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 -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/exons	MANE	Protein	UniProt
KLHL21	NM_014851.4	c.1500+101G>A		intron_variant		ENST00000377658.8	NP_055666.2
KLHL21	NM_001324309.2	c.1500+101G>A		intron_variant			NP_001311238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL21	ENST00000377658.8	c.1500+101G>A		intron_variant		1	NM_014851.4	ENSP00000366886.4

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3262 AN: 152190 Hom.: 64 Cov.: 33

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.: 56 AF XY: 0.0198 AC XY: 1981 AN XY: 100024

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.: 12 AF XY: 0.0245 AC XY: 11380 AN XY: 464148

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.: 64 Cov.: 33 AF XY: 0.0201 AC XY: 1494 AN XY: 74470

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.: 41

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: 6 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.97
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0029	T
MetaSVM	Uncertain	-0.25	T
PROVEAN	Benign	-0.020	N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.12
ClinPred		0.044	T
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

Other links and lift over

dbSNP: rs2232463; hg19: chr1-6655444; COSMIC: COSV66553922;