Genetic Variant KHDRBS2:p.Asp281Glu (chr6-61732732-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152688.4(KHDRBS2):c.843T>A(p.Asp281Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KHDRBS2
NM_152688.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.749

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14368972).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152688.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KHDRBS2	NM_152688.4	MANE Select	c.843T>A	p.Asp281Glu	missense	Exon 7 of 9	NP_689901.2	Q5VWX1
KHDRBS2	NM_001350622.2		c.894T>A	p.Asp298Glu	missense	Exon 8 of 10	NP_001337551.1
KHDRBS2	NR_146870.2		n.1120T>A		non_coding_transcript_exon	Exon 7 of 16

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KHDRBS2	ENST00000281156.5	TSL:1 MANE Select	c.843T>A	p.Asp281Glu	missense	Exon 7 of 9	ENSP00000281156.3	Q5VWX1
KHDRBS2	ENST00000968831.1		c.843T>A	p.Asp281Glu	missense	Exon 7 of 10	ENSP00000638890.1
KHDRBS2	ENST00000931671.1		c.696T>A	p.Asp232Glu	missense	Exon 6 of 8	ENSP00000601730.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459318

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726162

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.00

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109792

Other (OTH)

AF:

0.00

AC:

AN:

60296

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.031

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.66

M_CAP

Benign

0.0039

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.98

PhyloP100

0.75

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.61

REVEL

Benign

0.068

Sift

Benign

0.12

Sift4G

Benign

0.33

Polyphen

0.60

Vest4

0.27

MutPred

0.14

Gain of loop (P = 0.069)

MVP

0.41

MPC

0.059

ClinPred

0.34

GERP RS

-1.4

Varity_R

0.049

gMVP

0.28

Mutation Taster

=92/8

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over