rs1019445820

Variant names:

• chr17-45169601-T-G
• rs1019445820
• NM_001303441.2:c.653T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001303441.2(HEXIM2):​c.653T>G​(p.Leu218Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,388,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HEXIM2 NM_001303441.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

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.653T>G	p.Leu218Arg	missense	Exon 4 of 4	NP_001290370.1	Q96MH2
	HEXIM2	NM_001303436.1		c.719T>G	p.Leu240Arg	missense	Exon 3 of 3	NP_001290365.1	Q96MH2
	HEXIM2	NM_001303437.1		c.653T>G	p.Leu218Arg	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.653T>G	p.Leu218Arg	missense	Exon 4 of 4	ENSP00000466200.2	Q96MH2
	HEXIM2	ENST00000591576.5	TSL:1	c.653T>G	p.Leu218Arg	missense	Exon 3 of 3	ENSP00000465727.1	Q96MH2
	HEXIM2	ENST00000592695.1	TSL:1	c.653T>G	p.Leu218Arg	missense	Exon 3 of 3	ENSP00000467517.1	Q96MH2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1388778 Hom.: 0 Cov.: 30 AF XY: 0.00000292 AC XY: 2 AN XY: 684344

African (AFR) AF: 0.0000643 AC: 2 AN: 31100

American (AMR) AF: 0.00 AC: 0 AN: 33862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24534

East Asian (EAS) AF: 0.00 AC: 0 AN: 35642

South Asian (SAS) AF: 0.00 AC: 0 AN: 78910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073880

Other (OTH) AF: 0.00 AC: 0 AN: 57418

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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	Benign	0.25
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.28
Sift	Benign	0.046	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.79
MutPred		0.34		Gain of MoRF binding (P = 0.0137)
MVP		0.46
MPC		1.7
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.63
gMVP		0.50
Mutation Taster		=86/14	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: rs1019445820; hg19: chr17-43246968;