dbSNP rs570989300: KLHDC2:p.Trp383Arg (chr14-49782879-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014315.3(KLHDC2):c.1147T>A(p.Trp383Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KLHDC2
NM_014315.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.90

Variant links:

Genes affected

KLHDC2 (HGNC:20231): (kelch domain containing 2) Enables ubiquitin ligase-substrate adaptor activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Located in nuclear body and nuclear membrane. Is active in Cul2-RING ubiquitin ligase complex and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

KLHDC2 links:

NEMF (HGNC:10663): (nuclear export mediator factor) This gene encodes a component of the ribosome quality control complex. The encoded protein facilitates the recognition and ubiquitination of stalled 60S subunits by the ubiquitin ligase listerin. A similar protein in fly functions as a tumor suppressor. [provided by RefSeq, Jul 2016]

NEMF links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.789

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC2	NM_014315.3 link	c.1147T>A	p.Trp383Arg	missense_variant	Exon 13 of 13	ENST00000298307.10	NP_055130.1	Q9Y2U9-1
NEMF	NM_004713.6 link	c.*1757A>T		3_prime_UTR_variant	Exon 33 of 33	ENST00000298310.10	NP_004704.3	O60524-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC2	ENST00000298307.10 link	c.1147T>A	p.Trp383Arg	missense_variant	Exon 13 of 13	1	NM_014315.3	ENSP00000298307.5		Q9Y2U9-1
NEMF	ENST00000298310 link	c.*1757A>T		3_prime_UTR_variant	Exon 33 of 33	5	NM_004713.6	ENSP00000298310.5		O60524-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251172

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135740

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461546

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727090

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.72

M_CAP

Benign

0.042

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.6

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.28

Sift

Uncertain

0.022

Sift4G

Uncertain

0.059

Polyphen

0.92

Vest4

0.69

MutPred

0.69

Gain of disorder (P = 0.0127);

MVP

0.74

MPC

1.1

ClinPred

0.84

GERP RS

6.1

Varity_R

0.25

gMVP

0.78

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over