Genetic Variant NM_014997.4:c.202C>G (chr7-130096956-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014997.4(KLHDC10):c.202C>G(p.Arg68Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R68C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KLHDC10
NM_014997.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.56

Publications

0 publications found

Variant links:

Genes affected

KLHDC10 (HGNC:22194): (kelch domain containing 10) Enables ubiquitin ligase-substrate adaptor activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Located in nucleoplasm. Is active in Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

KLHDC10 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.091425866).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014997.4. 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
	KLHDC10	NM_014997.4	MANE Select	c.202C>G	p.Arg68Gly	missense	Exon 2 of 10	NP_055812.1	Q6PID8-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLHDC10	ENST00000335420.10	TSL:1 MANE Select	c.202C>G	p.Arg68Gly	missense	Exon 2 of 10	ENSP00000334140.4	Q6PID8-1
KLHDC10	ENST00000468226.1	TSL:3	c.-228C>G		5_prime_UTR	Exon 3 of 7	ENSP00000420034.1	C9JRX2
KLHDC10	ENST00000851918.1		c.71-19489C>G		intron	N/A	ENSP00000521977.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458952

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725790

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33432

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.00

AC:

AN:

85914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109954

Other (OTH)

AF:

0.0000166

AC:

AN:

60244

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.060

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.75

M_CAP

Benign

0.0028

MetaRNN

Benign

0.091

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

1.6

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.31

REVEL

Benign

0.078

Sift

Benign

0.49

Sift4G

Benign

0.47

Polyphen

0.023

Vest4

0.37

MutPred

0.44

Loss of stability (P = 0.06)

MVP

0.12

MPC

1.4

ClinPred

0.31

GERP RS

4.0

Varity_R

0.16

gMVP

0.53

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over