Variant 14-49779773-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014315.3(KLHDC2):c.740A>G(p.Tyr247Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000054 in 1,610,030 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 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

KLHDC2
NM_014315.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.87

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036603063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KLHDC2	NM_014315.3 linkuse as main transcript	c.740A>G	p.Tyr247Cys	missense_variant	8/13	ENST00000298307.10	NP_055130.1
KLHDC2	XM_006720094.5 linkuse as main transcript	c.740A>G	p.Tyr247Cys	missense_variant	8/13		XP_006720157.1
KLHDC2	XM_011536610.2 linkuse as main transcript	c.524A>G	p.Tyr175Cys	missense_variant	8/13		XP_011534912.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHDC2	ENST00000298307.10 linkuse as main transcript	c.740A>G	p.Tyr247Cys	missense_variant	8/13	1	NM_014315.3	ENSP00000298307	P1	Q9Y2U9-1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000517

AC:

AN:

251358

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000309

AC:

AN:

1457678

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

725352

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000831

GnomAD4 genome

AF:

0.000276

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.0000653

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

Alfa

AF:

0.000387

Hom.:

Bravo

AF:

0.000261

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

The c.740A>G (p.Y247C) alteration is located in exon 8 (coding exon 8) of the KLHDC2 gene. This alteration results from a A to G substitution at nucleotide position 740, causing the tyrosine (Y) at amino acid position 247 to be replaced by a cysteine (C). 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

0.052

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.072

T;T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.037

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.61

N;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.13

N;N;N

REVEL

Benign

0.065

Sift

Benign

0.31

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.30

MVP

0.55

MPC

0.39

ClinPred

0.056

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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