X-46472758-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001129898.2(KRBOX4):ā€‹c.262C>Gā€‹(p.Gln88Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000755 in 1,205,698 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000018 ( 0 hom., 0 hem., cov: 23)
Exomes š‘“: 0.000081 ( 0 hom. 31 hem. )

Consequence

KRBOX4
NM_001129898.2 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.66
Variant links:
Genes affected
KRBOX4 (HGNC:26007): (KRAB box domain containing 4) This encodes a zinc finger protein with an N-terminal KRAB (Kruppel-associated) domain found in transcriptional repressors. This gene is located in a region of the X chromosome thought to be involved in nonsyndromic X-linked cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.039812654).
BS2
High Hemizygotes in GnomAdExome4 at 31 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KRBOX4NM_001129898.2 linkc.262C>G p.Gln88Glu missense_variant 6/6 ENST00000344302.9 NP_001123370.1 Q5JUW0-1
KRBOX4NM_017776.3 linkc.247C>G p.Gln83Glu missense_variant 6/6 NP_060246.2 Q5JUW0-2
KRBOX4NM_001129899.2 linkc.*9C>G 3_prime_UTR_variant 7/7 NP_001123371.1 Q5JUW0-3
KRBOX4NM_001129900.2 linkc.*9C>G 3_prime_UTR_variant 7/7 NP_001123372.1 Q5JUW0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KRBOX4ENST00000344302.9 linkc.262C>G p.Gln88Glu missense_variant 6/62 NM_001129898.2 ENSP00000345797.4 Q5JUW0-1
KRBOX4ENST00000487081.1 linkc.*6C>G 3_prime_UTR_variant 6/61 ENSP00000418076.1 Q5JUW0-3
KRBOX4ENST00000298190.10 linkc.247C>G p.Gln83Glu missense_variant 6/62 ENSP00000298190.6 Q5JUW0-2
KRBOX4ENST00000478600.5 linkc.238+9465C>G intron_variant 2 ENSP00000418146.1 C9J950

Frequencies

GnomAD3 genomes
AF:
0.0000180
AC:
2
AN:
111301
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
33509
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:
0.000566
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:
0.0000393
AC:
7
AN:
178251
Hom.:
0
AF XY:
0.0000631
AC XY:
4
AN XY:
63431
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000511
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:
0.0000813
AC:
89
AN:
1094397
Hom.:
0
Cov.:
30
AF XY:
0.0000860
AC XY:
31
AN XY:
360313
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00292
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000180
AC:
2
AN:
111301
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
33509
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000566
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

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 22, 2024The c.262C>G (p.Q88E) alteration is located in exon 6 (coding exon 4) of the KRBOX4 gene. This alteration results from a C to G substitution at nucleotide position 262, causing the glutamine (Q) at amino acid position 88 to be replaced by a glutamic acid (E). 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
0.077
BayesDel_addAF
Benign
-0.69
T
BayesDel_noAF
Benign
-0.88
CADD
Benign
6.7
DANN
Benign
0.97
DEOGEN2
Benign
0.013
T;.
FATHMM_MKL
Benign
0.063
N
LIST_S2
Benign
0.012
T;T
M_CAP
Benign
0.0039
T
MetaRNN
Benign
0.040
T;T
MetaSVM
Benign
-0.76
T
MutationAssessor
Benign
0.47
N;.
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.037
Sift
Benign
0.22
T;T
Sift4G
Benign
0.47
T;T
Polyphen
0.0010
B;B
Vest4
0.12
MutPred
0.34
Gain of loop (P = 0.0166);.;
MVP
0.58
MPC
0.48
ClinPred
0.048
T
GERP RS
1.5
Varity_R
0.24
gMVP
0.035

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs751467099; hg19: chrX-46332193; COSMIC: COSV53344075; COSMIC: COSV53344075; API