chr17-45169540-G-C

Variant names:

• chr17-45169540-G-C
• rs775048819
• NM_001303441.2:c.592G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001303441.2(HEXIM2):​c.592G>C​(p.Glu198Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000114 in 1,578,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: HEXIM2 NM_001303441.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.63
• Publications: 2 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12839845).

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.592G>C	p.Glu198Gln	missense	Exon 4 of 4	NP_001290370.1	Q96MH2
	HEXIM2	NM_001303436.1		c.658G>C	p.Glu220Gln	missense	Exon 3 of 3	NP_001290365.1	Q96MH2
	HEXIM2	NM_001303437.1		c.592G>C	p.Glu198Gln	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.592G>C	p.Glu198Gln	missense	Exon 4 of 4	ENSP00000466200.2	Q96MH2
	HEXIM2	ENST00000591576.5	TSL:1	c.592G>C	p.Glu198Gln	missense	Exon 3 of 3	ENSP00000465727.1	Q96MH2
	HEXIM2	ENST00000592695.1	TSL:1	c.592G>C	p.Glu198Gln	missense	Exon 3 of 3	ENSP00000467517.1	Q96MH2

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 151916 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000218 AC: 41 AN: 188118 AF XY: 0.000217

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00361

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000501

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000116 AC: 165 AN: 1426888 Hom.: 0 Cov.: 31 AF XY: 0.000115 AC XY: 81 AN XY: 707056

African (AFR) AF: 0.0000614 AC: 2 AN: 32552

American (AMR) AF: 0.000181 AC: 7 AN: 38580

Ashkenazi Jewish (ASJ) AF: 0.00428 AC: 109 AN: 25454

East Asian (EAS) AF: 0.00 AC: 0 AN: 37556

South Asian (SAS) AF: 0.00 AC: 0 AN: 82418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50412

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5718

European-Non Finnish (NFE) AF: 0.0000274 AC: 30 AN: 1095064

Other (OTH) AF: 0.000254 AC: 15 AN: 59134

GnomAD4 genome AF: 0.0000987 AC: 15 AN: 151916 Hom.: 0 Cov.: 31 AF XY: 0.0000943 AC XY: 7 AN XY: 74216

African (AFR) AF: 0.0000242 AC: 1 AN: 41350

American (AMR) AF: 0.000131 AC: 2 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000406 Hom.: 0

Bravo AF: 0.000162

ExAC AF: 0.000126 AC: 15

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	0.23
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.32
Sift	Benign	0.056	T
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.48		Gain of MoRF binding (P = 0.029)
MVP		0.69
MPC		1.4
ClinPred		0.54	D
GERP RS		4.6
Varity_R		0.43
gMVP		0.25
Mutation Taster		=77/23	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: rs775048819; hg19: chr17-43246907;