17-45169601-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ENSG00000267288 (HGNC:56693):

LOC105371795 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXIM2	NM_001303441.2	c.653T>G	p.Leu218Arg	missense_variant	Exon 4 of 4	ENST00000589230.6	NP_001290370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXIM2	ENST00000589230.6	c.653T>G	p.Leu218Arg	missense_variant	Exon 4 of 4	2	NM_001303441.2	ENSP00000466200.2

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

Gnomad4 AFR exome AF: 0.0000643

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 Cov.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.653T>G (p.L218R) alteration is located in exon 4 (coding exon 2) of the HEXIM2 gene. This alteration results from a T to G substitution at nucleotide position 653, causing the leucine (L) at amino acid position 218 to be replaced by an arginine (R). 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	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;T;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;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.4	M;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.7	D;.;.
REVEL	Benign	0.28
Sift	Benign	0.046	D;.;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.98	D;D;D
Vest4		0.79
MutPred		0.34		Gain of MoRF binding (P = 0.0137);Gain of MoRF binding (P = 0.0137);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

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

Other links and lift over

dbSNP: rs1019445820; hg19: chr17-43246968;