Genetic Variant KLHDC8B:p.Ala55Val (chr3-49172933-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_173546.3(KLHDC8B):c.164C>T(p.Ala55Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

KLHDC8B
NM_173546.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.144

Variant links:

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]

KLHDC8B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08918747).

BS2

High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC8B	NM_173546.3 link	c.164C>T	p.Ala55Val	missense_variant	Exon 2 of 6	ENST00000332780.4	NP_775817.1	Q8IXV7Q96DZ8
KLHDC8B	XM_006713015.4 link	c.164C>T	p.Ala55Val	missense_variant	Exon 2 of 6		XP_006713078.1
KLHDC8B	XM_006713016.4 link	c.164C>T	p.Ala55Val	missense_variant	Exon 2 of 6		XP_006713079.1
KLHDC8B	XM_005264938.4 link	c.164C>T	p.Ala55Val	missense_variant	Exon 2 of 6		XP_005264995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLHDC8B	ENST00000332780.4 link	c.164C>T	p.Ala55Val	missense_variant	Exon 2 of 6	1	NM_173546.3	ENSP00000327468.2	Q8IXV7
KLHDC8B	ENST00000476495.2 link	n.221C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2
KLHDC8B	ENST00000459846.6 link	n.230+132C>T		intron_variant	Intron 2 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251104

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000624

Hom.:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.164C>T (p.A55V) alteration is located in exon 2 (coding exon 1) of the KLHDC8B gene. This alteration results from a C to T substitution at nucleotide position 164, causing the alanine (A) at amino acid position 55 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.67

M_CAP

Benign

0.0060

MetaRNN

Benign

0.089

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.16

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.3

REVEL

Benign

0.014

Sift

Benign

0.12

Sift4G

Benign

0.99

Polyphen

0.016

Vest4

0.055

MutPred

0.36

Loss of disorder (P = 0.0926);

MVP

0.49

MPC

0.44

ClinPred

0.052

GERP RS

3.5

Varity_R

0.058

gMVP

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over