Genetic Variant HEXIM2:p.Arg279Pro (chr17-45169784-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001303441.2(HEXIM2):c.836G>C(p.Arg279Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000771 in 1,296,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R279H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

HEXIM2
NM_001303441.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.700

Publications

0 publications found

Variant links:

Genes affected

HEXIM2 (HGNC:28591): (HEXIM P-TEFb complex subunit 2) This gene encodes a member of the HEXIM family of proteins. This protein is a component of the 7SK small nuclear ribonucleoprotein. This protein has been found to negatively regulate the kinase activity of the cyclin-dependent kinase P-TEFb, which phosphorylates multiple target proteins to promote transcriptional elongation. This gene is located approximately 7 kb downstream from related family member HEXIM1 on chromosome 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

HEXIM2 links:

HEXIM2-AS2 (HGNC:56693):

HEXIM2-AS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04544145).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001303441.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HEXIM2	NM_001303441.2	MANE Select	c.836G>C	p.Arg279Pro	missense	Exon 4 of 4	NP_001290370.1	Q96MH2
HEXIM2	NM_001303436.1		c.902G>C	p.Arg301Pro	missense	Exon 3 of 3	NP_001290365.1	Q96MH2
HEXIM2	NM_001303437.1		c.836G>C	p.Arg279Pro	missense	Exon 4 of 4	NP_001290366.1	Q96MH2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HEXIM2	ENST00000589230.6	TSL:2 MANE Select	c.836G>C	p.Arg279Pro	missense	Exon 4 of 4	ENSP00000466200.2	Q96MH2
HEXIM2	ENST00000591576.5	TSL:1	c.836G>C	p.Arg279Pro	missense	Exon 3 of 3	ENSP00000465727.1	Q96MH2
HEXIM2	ENST00000592695.1	TSL:1	c.836G>C	p.Arg279Pro	missense	Exon 3 of 3	ENSP00000467517.1	Q96MH2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.71e-7

AC:

AN:

1296250

Hom.:

Cov.:

AF XY:

0.00000159

AC XY:

AN XY:

629248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28528

American (AMR)

AF:

0.00

AC:

AN:

21464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19346

East Asian (EAS)

AF:

0.00

AC:

AN:

34826

South Asian (SAS)

AF:

0.00

AC:

AN:

64780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5064

European-Non Finnish (NFE)

AF:

9.67e-7

AC:

AN:

1033996

Other (OTH)

AF:

0.00

AC:

AN:

53796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.53

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.0091

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.32

M_CAP

Benign

0.0054

MetaRNN

Benign

0.045

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-0.70

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.010

REVEL

Benign

0.0020

Sift

Benign

0.24

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.15

MutPred

0.22

Loss of MoRF binding (P = 0.0083)

MVP

0.21

MPC

0.74

ClinPred

0.052

GERP RS

-1.9

Varity_R

0.087

gMVP

0.050

Mutation Taster

=94/6

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

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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