3-49173048-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_173546.3(KLHDC8B):c.279G>A(p.Pro93=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000515 in 1,609,774 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (16 hom.)
• Consequence: KLHDC8B NM_173546.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.04

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 3-49173048-G-A is Benign according to our data. Variant chr3-49173048-G-A is described in ClinVar as [Benign]. Clinvar id is 2058265.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.04 with no splicing effect.
• BS2: High AC in GnomAd at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHDC8B	NM_173546.3	c.279G>A	p.Pro93=	synonymous_variant	2/6	ENST00000332780.4
KLHDC8B	XM_006713015.4	c.279G>A	p.Pro93=	synonymous_variant	2/6
KLHDC8B	XM_006713016.4	c.279G>A	p.Pro93=	synonymous_variant	2/6
KLHDC8B	XM_005264938.4	c.279G>A	p.Pro93=	synonymous_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHDC8B	ENST00000332780.4	c.279G>A	p.Pro93=	synonymous_variant	2/6	1	NM_173546.3	P1
KLHDC8B	ENST00000476495.2	n.336G>A		non_coding_transcript_exon_variant	1/3	2
KLHDC8B	ENST00000459846.6	n.230+247G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00104 AC: 250 AN: 240276 Hom.: 8 AF XY: 0.00133 AC XY: 173 AN XY: 130488

Gnomad AFR exome AF: 0.0000657

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00742

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000537 AC: 783 AN: 1457496 Hom.: 16 Cov.: 31 AF XY: 0.000733 AC XY: 531 AN XY: 724880

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00643

Gnomad4 FIN exome AF: 0.0000568

Gnomad4 NFE exome AF: 0.000159

Gnomad4 OTH exome AF: 0.000831

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74448

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00706

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000107 Hom.: 1

Bravo AF: 0.000128

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 30, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	2.8
Dann	Benign	0.85

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: rs556212641; hg19: chr3-49210481; COSMIC: COSV60412880; COSMIC: COSV60412880;