Genetic Variant KLHDC9:p.Pro78Leu (chr1-161098768-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152366.5(KLHDC9):c.233C>T(p.Pro78Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,518 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P78Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KLHDC9
NM_152366.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.535

Publications

0 publications found

Variant links:

Genes affected

KLHDC9 (HGNC:28489): (kelch domain containing 9) Enables cyclin binding activity. [provided by Alliance of Genome Resources, Apr 2022]

KLHDC9 links:

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ACMG classification

Classification was made for transcript

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=0.06255734).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152366.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLHDC9	NM_152366.5	MANE Select	c.233C>T	p.Pro78Leu	missense	Exon 1 of 4	NP_689579.3
KLHDC9	NM_001007255.3		c.233C>T	p.Pro78Leu	missense	Exon 1 of 4	NP_001007256.1	Q8NEP7-2
KLHDC9	NR_033385.2		n.147C>T		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLHDC9	ENST00000368011.9	TSL:1 MANE Select	c.233C>T	p.Pro78Leu	missense	Exon 1 of 4	ENSP00000356990.4	Q8NEP7-1
KLHDC9	ENST00000392192.6	TSL:1	c.233C>T	p.Pro78Leu	missense	Exon 1 of 4	ENSP00000376030.2	Q8NEP7-2
KLHDC9	ENST00000917942.1		c.233C>T	p.Pro78Leu	missense	Exon 1 of 4	ENSP00000588001.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

219158

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1447518

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718992

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33066

American (AMR)

AF:

0.00

AC:

AN:

42736

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25794

East Asian (EAS)

AF:

0.00

AC:

AN:

38736

South Asian (SAS)

AF:

0.00

AC:

AN:

84564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1105018

Other (OTH)

AF:

0.0000168

AC:

AN:

59676

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.7

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0097

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.49

M_CAP

Benign

0.039

MetaRNN

Benign

0.063

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.49

PhyloP100

-0.54

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.9

REVEL

Benign

0.16

Sift

Benign

0.44

Sift4G

Benign

0.32

Polyphen

0.0

Vest4

0.087

MutPred

0.33

Loss of catalytic residue at P77 (P = 0.0144)

MVP

0.072

MPC

0.31

ClinPred

0.11

GERP RS

0.99

PromoterAI

0.085

Neutral

(source)

Varity_R

0.033

gMVP

0.71

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over