rs2230804

Variant names:

• chr10-100218126-C-T
• rs2230804
• NM_001278.5:c.802G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001278.5(CHUK):​c.802G>A​(p.Val268Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 1,605,460 control chromosomes in the GnomAD database, including 213,829 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.56 (25191 hom., cov: 31)
  • Exomes 𝑓: 0.50 (188638 hom.)
• Consequence: CHUK NM_001278.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.14

Genes affected

CHUK (HGNC:1974): (component of inhibitor of nuclear factor kappa B kinase complex) This gene encodes a member of the serine/threonine protein kinase family. The encoded protein, a component of a cytokine-activated protein complex that is an inhibitor of the essential transcription factor NF-kappa-B complex, phosphorylates sites that trigger the degradation of the inhibitor via the ubiquination pathway, thereby activating the transcription factor. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.5614154E-6).
• BP6: Variant 10-100218126-C-T is Benign according to our data. Variant chr10-100218126-C-T is described in ClinVar as [Benign]. Clinvar id is 1221248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100218126-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHUK	NM_001278.5	c.802G>A	p.Val268Ile	missense_variant	Exon 9 of 21	ENST00000370397.8	NP_001269.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHUK	ENST00000370397.8	c.802G>A	p.Val268Ile	missense_variant	Exon 9 of 21	1	NM_001278.5	ENSP00000359424.6

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85443 AN: 151848 Hom.: 25155 Cov.: 31

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.541

GnomAD3 exomes AF: 0.474 AC: 118957 AN: 251076 Hom.: 29579 AF XY: 0.468 AC XY: 63453 AN XY: 135722

Gnomad AFR exome AF: 0.751

Gnomad AMR exome AF: 0.364

Gnomad ASJ exome AF: 0.430

Gnomad EAS exome AF: 0.487

Gnomad SAS exome AF: 0.336

Gnomad FIN exome AF: 0.460

Gnomad NFE exome AF: 0.508

Gnomad OTH exome AF: 0.488

GnomAD4 exome AF: 0.504 AC: 732639 AN: 1453494 Hom.: 188638 Cov.: 33 AF XY: 0.499 AC XY: 360835 AN XY: 723620

Gnomad4 AFR exome AF: 0.758

Gnomad4 AMR exome AF: 0.376

Gnomad4 ASJ exome AF: 0.424

Gnomad4 EAS exome AF: 0.480

Gnomad4 SAS exome AF: 0.336

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.519

Gnomad4 OTH exome AF: 0.514

GnomAD4 genome AF: 0.563 AC: 85532 AN: 151966 Hom.: 25191 Cov.: 31 AF XY: 0.557 AC XY: 41328 AN XY: 74254

Gnomad4 AFR AF: 0.750

Gnomad4 AMR AF: 0.464

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.491

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.466

Gnomad4 NFE AF: 0.513

Gnomad4 OTH AF: 0.543

Alfa AF: 0.516 Hom.: 43570

Bravo AF: 0.571

TwinsUK AF: 0.529 AC: 1962

ALSPAC AF: 0.516 AC: 1988

ESP6500AA AF: 0.743 AC: 3274

ESP6500EA AF: 0.501 AC: 4309

ExAC AF: 0.479 AC: 58144

Asia WGS AF: 0.462 AC: 1607 AN: 3478

EpiCase AF: 0.509

EpiControl AF: 0.514

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 74% of patients studied by a panel of primary immunodeficiencies. Number of patients: 70. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0000066	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.60	N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.13
Sift	Benign	0.38	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.45
ClinPred		0.013	T
GERP RS		4.9
Varity_R		0.027
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2230804; hg19: chr10-101977883; COSMIC: COSV64917551;