Variant 6-73241660-C-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 ENST00000257765.10(KHDC1):c.364G>C(p.Val122Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000886 in 1,614,164 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 1 hom. )

Consequence

KHDC1
ENST00000257765.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -1.78

Variant links:

Genes affected

KHDC1 (HGNC:21366): (KH domain containing 1) Predicted to enable identical protein binding activity and poly(U) RNA binding activity. Predicted to be involved in activation of cysteine-type endopeptidase activity involved in apoptotic process. Predicted to be integral component of membrane. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

KHDC1 links:

LOC122539213 (HGNC:):

LOC122539213 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=0.020164073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHDC1	NM_030568.5 linkuse as main transcript	c.364G>C	p.Val122Leu	missense_variant	4/4	ENST00000257765.10	NP_085045.3
LOC122539213	NR_173146.1 linkuse as main transcript	n.959+395G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KHDC1	ENST00000257765.10 linkuse as main transcript	c.364G>C	p.Val122Leu	missense_variant	4/4	1	NM_030568.5	ENSP00000257765	P2	Q4VXA5-2
KHDC1	ENST00000370384.7 linkuse as main transcript	c.583G>C	p.Val195Leu	missense_variant	5/5	1		ENSP00000359411	A2	Q4VXA5-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000120

AC:

AN:

249510

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

135366

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000972

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.0000903

AC:

132

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000949

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000854

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000992

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2022

The c.364G>C (p.V122L) alteration is located in exon 4 (coding exon 3) of the KHDC1 gene. This alteration results from a G to C substitution at nucleotide position 364, causing the valine (V) at amino acid position 122 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.0050

DANN

Benign

0.47

DEOGEN2

Benign

0.0011

.;T;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.46

.;T;T;T

M_CAP

Benign

0.00078

MetaRNN

Benign

0.020

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.83

.;L;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.29

N;N;.;.

REVEL

Benign

0.0040

Sift

Benign

1.0

T;.;.;.

Sift4G

Benign

0.48

T;T;T;T

Polyphen

0.0050

.;B;.;.

Vest4

0.076

MutPred

0.19

.;Loss of sheet (P = 0.1158);.;.;

MVP

0.014

MPC

0.043

ClinPred

0.0055

GERP RS

-4.4

Varity_R

0.11

gMVP

0.0082

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over