3-49172891-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_173546.3(KLHDC8B):c.122G>A(p.Arg41Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: KLHDC8B NM_173546.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.273

Genes affected

KLHDC8B (HGNC:28557): (kelch domain containing 8B) This gene encodes a protein which forms a distinct beta-propeller protein structure of kelch domains allowing for protein-protein interactions. Mutations in this gene have been associated with Hodgkin lymphoma. [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.036590546).
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHDC8B	NM_173546.3	c.122G>A	p.Arg41Gln	missense_variant	2/6	ENST00000332780.4
KLHDC8B	XM_006713015.4	c.122G>A	p.Arg41Gln	missense_variant	2/6
KLHDC8B	XM_006713016.4	c.122G>A	p.Arg41Gln	missense_variant	2/6
KLHDC8B	XM_005264938.4	c.122G>A	p.Arg41Gln	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHDC8B	ENST00000332780.4	c.122G>A	p.Arg41Gln	missense_variant	2/6	1	NM_173546.3	P1
KLHDC8B	ENST00000476495.2	n.179G>A		non_coding_transcript_exon_variant	1/3	2
KLHDC8B	ENST00000459846.6	n.230+90G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250828 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135658

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727210

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74498

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 25, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with KLHDC8B-related conditions. This variant is present in population databases (rs373852462, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 41 of the KLHDC8B protein (p.Arg41Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	14
Dann	Benign	0.93
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.37	N
MutationTaster	Benign	0.94	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.046
Sift	Benign	0.58	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.23
MPC		0.51
ClinPred		0.011	T
GERP RS		-2.3
Varity_R		0.044
gMVP		0.23

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: rs373852462; hg19: chr3-49210324; COSMIC: COSV100234380; COSMIC: COSV100234380;