Genetic Variant HEXIM2:p.Asn263Lys (chr17-45169737-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001303441.2(HEXIM2):c.789C>A(p.Asn263Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000134 in 1,488,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

HEXIM2
NM_001303441.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.96

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:

ENSG00000267288 (HGNC:56693):

ENSG00000267288 links:

LOC105371795 (HGNC:):

LOC105371795 links:

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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
HEXIM2	NM_001303441.2 link	c.789C>A	p.Asn263Lys	missense_variant	Exon 4 of 4	ENST00000589230.6	NP_001290370.1	Q96MH2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXIM2	ENST00000589230.6 link	c.789C>A	p.Asn263Lys	missense_variant	Exon 4 of 4	2	NM_001303441.2	ENSP00000466200.2		Q96MH2K7ELS4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

AF:

7.48e-7

AC:

AN:

1336852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

653684

show subpopulations

Gnomad4 AFR exome

AF:

0.0000341

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.789C>A (p.N263K) alteration is located in exon 4 (coding exon 2) of the HEXIM2 gene. This alteration results from a C to A substitution at nucleotide position 789, causing the asparagine (N) at amino acid position 263 to be replaced by a lysine (K). 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

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.77

.;.;T

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.73

D;D;D

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.3

M;M;M

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.7

D;.;.

REVEL

Benign

0.12

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.77

MutPred

0.12

Gain of ubiquitination at N263 (P = 0.0101);Gain of ubiquitination at N263 (P = 0.0101);Gain of ubiquitination at N263 (P = 0.0101);

MVP

0.61

MPC

1.5

ClinPred

1.0

GERP RS

4.5

Varity_R

0.81

gMVP

0.68

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