6-61894702-C-T

Variant summary

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

The NM_152688.4(KHDRBS2):​c.743G>A​(p.Arg248Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000171 in 1,461,204 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R248W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

KHDRBS2
NM_152688.4 missense

Scores

3
6
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59
Variant links:
Genes affected
KHDRBS2 (HGNC:18114): (KH RNA binding domain containing, signal transduction associated 2) Predicted to enable mRNA binding activity and poly(A) binding activity. Predicted to be involved in regulation of alternative mRNA splicing, via spliceosome. Predicted to be located in nucleoplasm. Predicted to be active in nucleus. [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 rank MANE Protein UniProt
KHDRBS2NM_152688.4 linkc.743G>A p.Arg248Gln missense_variant Exon 6 of 9 ENST00000281156.5 NP_689901.2 Q5VWX1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KHDRBS2ENST00000281156.5 linkc.743G>A p.Arg248Gln missense_variant Exon 6 of 9 1 NM_152688.4 ENSP00000281156.3 Q5VWX1
KHDRBS2ENST00000675091.1 linkn.743G>A non_coding_transcript_exon_variant Exon 6 of 10 ENSP00000502245.1 A0A6Q8PGH5

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
250260
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135290
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461204
Hom.:
0
Cov.:
31
AF XY:
0.0000234
AC XY:
17
AN XY:
726864
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.0000189
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
31
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000594

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 30, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.743G>A (p.R248Q) alteration is located in exon 6 (coding exon 6) of the KHDRBS2 gene. This alteration results from a G to A substitution at nucleotide position 743, causing the arginine (R) at amino acid position 248 to be replaced by a glutamine (Q). 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
0.24
BayesDel_addAF
Benign
-0.026
T
BayesDel_noAF
Benign
-0.28
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.17
T
Eigen
Uncertain
0.65
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Pathogenic
0.97
D
M_CAP
Benign
0.017
T
MetaRNN
Uncertain
0.63
D
MetaSVM
Benign
-0.83
T
MutationAssessor
Uncertain
2.4
M
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-2.2
N
REVEL
Benign
0.18
Sift
Uncertain
0.013
D
Sift4G
Benign
0.095
T
Polyphen
0.99
D
Vest4
0.58
MutPred
0.31
Loss of methylation at R248 (P = 0.0047);
MVP
0.77
MPC
0.092
ClinPred
0.89
D
GERP RS
5.8
Varity_R
0.30
gMVP
0.48

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: rs747431309; hg19: chr6-62604607; COSMIC: COSV99831215; API