Genetic Variant KHDRBS2:p.Pro332Thr (chr6-61681019-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_152688.4(KHDRBS2):c.994C>A(p.Pro332Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KHDRBS2
NM_152688.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.23

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]

KHDRBS2 links:

KHDRBS2-OT1 (HGNC:):

KHDRBS2-OT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3876322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHDRBS2	NM_152688.4 link	c.994C>A	p.Pro332Thr	missense_variant	Exon 9 of 9	ENST00000281156.5	NP_689901.2	Q5VWX1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KHDRBS2	ENST00000281156.5 link	c.994C>A	p.Pro332Thr	missense_variant	Exon 9 of 9	1	NM_152688.4	ENSP00000281156.3	Q5VWX1
KHDRBS2-OT1	ENST00000511849.2 link	n.31C>A		non_coding_transcript_exon_variant	Exon 1 of 6	3
KHDRBS2	ENST00000675091.1 link	n.*150C>A		non_coding_transcript_exon_variant	Exon 10 of 10			ENSP00000502245.1	A0A6Q8PGH5
KHDRBS2	ENST00000675091.1 link	n.*150C>A		3_prime_UTR_variant	Exon 10 of 10			ENSP00000502245.1	A0A6Q8PGH5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248766

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134670

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

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:

0.00000137

AC:

AN:

1459934

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726360

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.994C>A (p.P332T) alteration is located in exon 9 (coding exon 9) of the KHDRBS2 gene. This alteration results from a C to A substitution at nucleotide position 994, causing the proline (P) at amino acid position 332 to be replaced by a threonine (T). 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

0.084

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.038

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.25

Sift

Benign

0.30

Sift4G

Benign

0.32

Polyphen

1.0

Vest4

0.20

MutPred

0.36

Gain of phosphorylation at P332 (P = 0.0056);

MVP

0.61

MPC

0.30

ClinPred

0.95

GERP RS

4.2

Varity_R

0.30

gMVP

0.55

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