rs2230804

Positions:

• chr10-100218126-C-T

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 same amino acid change has been previously reported as Likely benignin 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/exons	MANE	Protein	UniProt
CHUK	NM_001278.5	c.802G>A	p.Val268Ile	missense_variant	9/21	ENST00000370397.8	NP_001269.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHUK	ENST00000370397.8	c.802G>A	p.Val268Ile	missense_variant	9/21	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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

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;