rs1277287142

Variant names:

• chr17-45169737-C-A
• rs1277287142
• NM_001303441.2:c.789C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.96
• Publications: 0 publications found

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-AS2 (HGNC:56693):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXIM2	NM_001303441.2	MANE Select	c.789C>A	p.Asn263Lys	missense	Exon 4 of 4	NP_001290370.1	Q96MH2
	HEXIM2	NM_001303436.1		c.855C>A	p.Asn285Lys	missense	Exon 3 of 3	NP_001290365.1	Q96MH2
	HEXIM2	NM_001303437.1		c.789C>A	p.Asn263Lys	missense	Exon 4 of 4	NP_001290366.1	Q96MH2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXIM2	ENST00000589230.6	TSL:2 MANE Select	c.789C>A	p.Asn263Lys	missense	Exon 4 of 4	ENSP00000466200.2	Q96MH2
	HEXIM2	ENST00000591576.5	TSL:1	c.789C>A	p.Asn263Lys	missense	Exon 3 of 3	ENSP00000465727.1	Q96MH2
	HEXIM2	ENST00000592695.1	TSL:1	c.789C>A	p.Asn263Lys	missense	Exon 3 of 3	ENSP00000467517.1	Q96MH2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152102 Hom.: 0 Cov.: 31

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: 1 AN: 1336852 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 653684

African (AFR) AF: 0.0000341 AC: 1 AN: 29340

American (AMR) AF: 0.00 AC: 0 AN: 25850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21676

East Asian (EAS) AF: 0.00 AC: 0 AN: 35090

South Asian (SAS) AF: 0.00 AC: 0 AN: 71870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5374

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1049992

Other (OTH) AF: 0.00 AC: 0 AN: 55182

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152102 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.12		Gain of ubiquitination at N263 (P = 0.0101)
MVP		0.61
MPC		1.5
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.81
gMVP		0.68
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs1277287142; hg19: chr17-43247104;