rs2232463

Variant names:

• chr1-6595384-C-T
• rs2232463
• ENST00000377663.3:c.1601G>A

Variant summary

Our verdict is Benign. The variant received -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. 12/16 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
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 64 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000377663.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL21	NM_014851.4	MANE Select	c.1500+101G>A		intron	N/A	NP_055666.2
	KLHL21	NM_001324309.2		c.1500+101G>A		intron	N/A	NP_001311238.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL21	ENST00000377663.3	TSL:1	c.1601G>A	p.Gly534Asp	missense	Exon 3 of 3	ENSP00000366891.3	Q9UJP4-2
	KLHL21	ENST00000377658.8	TSL:1 MANE Select	c.1500+101G>A		intron	N/A	ENSP00000366886.4	Q9UJP4-1
	KLHL21	ENST00000496707.5	TSL:1	c.399+101G>A		intron	N/A	ENSP00000468710.1	K7ESH2

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

GnomAD2 exomes AF: 0.0201 AC: 3751 AN: 186952 AF XY: 0.0198

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 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

African (AFR) AF: 0.00533 AC: 118 AN: 22124

American (AMR) AF: 0.0186 AC: 694 AN: 37338

Ashkenazi Jewish (ASJ) AF: 0.00601 AC: 133 AN: 22132

East Asian (EAS) AF: 0.0000286 AC: 1 AN: 34916

South Asian (SAS) AF: 0.00371 AC: 264 AN: 71246

European-Finnish (FIN) AF: 0.0254 AC: 1288 AN: 50754

Middle Eastern (MID) AF: 0.00276 AC: 13 AN: 4708

European-Non Finnish (NFE) AF: 0.0314 AC: 19169 AN: 611104

Other (OTH) AF: 0.0221 AC: 924 AN: 41720

GnomAD4 genome AF: 0.0214 AC: 3262 AN: 152308 Hom.: 64 Cov.: 33 AF XY: 0.0201 AC XY: 1494 AN XY: 74470

African (AFR) AF: 0.00609 AC: 253 AN: 41568

American (AMR) AF: 0.0233 AC: 356 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4822

European-Finnish (FIN) AF: 0.0210 AC: 223 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0333 AC: 2262 AN: 68016

Other (OTH) AF: 0.0198 AC: 42 AN: 2116

Alfa AF: 0.0277 Hom.: 145

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
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
PhyloP100		1.3
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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