3-49172940-C-G

Variant names:

• chr3-49172940-C-G
• rs758765503
• NM_173546.3:c.171C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173546.3(KLHDC8B):​c.171C>G​(p.His57Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H57Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KLHDC8B NM_173546.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.112
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• classic Hodgkin lymphoma

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060916096).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173546.3. 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
	KLHDC8B	NM_173546.3	MANE Select	c.171C>G	p.His57Gln	missense	Exon 2 of 6	NP_775817.1	Q8IXV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHDC8B	ENST00000332780.4	TSL:1 MANE Select	c.171C>G	p.His57Gln	missense	Exon 2 of 6	ENSP00000327468.2	Q8IXV7
	KLHDC8B	ENST00000948547.1		c.171C>G	p.His57Gln	missense	Exon 2 of 6	ENSP00000618606.1
	KLHDC8B	ENST00000948549.1		c.171C>G	p.His57Gln	missense	Exon 2 of 6	ENSP00000618608.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251080 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461734 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.63	N
PhyloP100		-0.11
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.13
Sift	Benign	0.31	T
Sift4G	Benign	0.60	T
Polyphen		0.0030	B
Vest4		0.074
MutPred		0.45		Loss of glycosylation at S56 (P = 0.1002)
MVP		0.39
MPC		0.44
ClinPred		0.061	T
GERP RS		-0.41
Varity_R		0.14
gMVP		0.39
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs758765503; hg19: chr3-49210373;