6-73242148-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030568.5(KHDC1):​c.202C>T​(p.Arg68Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

KHDC1
NM_030568.5 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0610
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KHDC1NM_030568.5 linkc.202C>T p.Arg68Cys missense_variant 3/4 ENST00000257765.10 NP_085045.3 Q4VXA5-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KHDC1ENST00000257765.10 linkc.202C>T p.Arg68Cys missense_variant 3/41 NM_030568.5 ENSP00000257765.5 Q4VXA5-2
KHDC1ENST00000370384.7 linkc.421C>T p.Arg141Cys missense_variant 4/51 ENSP00000359411.3 Q4VXA5-1
ENSG00000243501ENST00000423730.3 linkn.202C>T non_coding_transcript_exon_variant 3/85 ENSP00000457270.2 F5H697
KHDC1ENST00000433730.1 linkc.202C>T p.Arg68Cys missense_variant 3/33 ENSP00000406966.1 A6PVU5

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
249294
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135256
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000111
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461866
Hom.:
0
Cov.:
32
AF XY:
0.00000688
AC XY:
5
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2

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 submitterclinical testingAmbry GeneticsJan 06, 2023The c.202C>T (p.R68C) alteration is located in exon 3 (coding exon 2) of the KHDC1 gene. This alteration results from a C to T substitution at nucleotide position 202, causing the arginine (R) at amino acid position 68 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
0.25
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.043
.;T;.;.;.
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.56
FATHMM_MKL
Benign
0.0086
N
LIST_S2
Benign
0.79
.;T;T;T;T
M_CAP
Benign
0.0060
T
MetaRNN
Uncertain
0.53
D;D;D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
.;L;.;.;.
PrimateAI
Benign
0.36
T
PROVEAN
Pathogenic
-5.5
D;D;.;.;D
REVEL
Benign
0.21
Sift
Benign
0.059
T;.;.;.;T
Sift4G
Uncertain
0.049
D;D;T;D;.
Polyphen
1.0
.;D;.;.;.
Vest4
0.33
MutPred
0.81
.;Loss of MoRF binding (P = 0.0292);.;.;.;
MVP
0.23
MPC
0.073
ClinPred
0.62
D
GERP RS
1.0
Varity_R
0.67
gMVP
0.074

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.

Other links and lift over

dbSNP: rs773192554; hg19: chr6-73951871; COSMIC: COSV57614322; API