19-12792009-C-T

Position:

• chr19-12792009-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002229.3(JUNB):​c.238C>T​(p.Leu80Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: JUNB NM_002229.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.95

Genes affected

JUNB (HGNC:6205): (JunB proto-oncogene, AP-1 transcription factor subunit) Enables sequence-specific double-stranded DNA binding activity. Involved in positive regulation of transcription by RNA polymerase II. Located in nucleoplasm. Part of transcription factor AP-1 complex. Biomarker of Hodgkin's lymphoma and anaplastic large cell lymphoma. [provided by Alliance of Genome Resources, Apr 2022]

HOOK2 (HGNC:19885): (hook microtubule tethering protein 2) Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.[supplied by OMIM, Apr 2004]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JUNB	NM_002229.3	c.238C>T	p.Leu80Phe	missense_variant	1/1	ENST00000302754.6	NP_002220.1
HOOK2	NM_001400043.1	c.-209+315G>A		intron_variant			NP_001386972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JUNB	ENST00000302754.6	c.238C>T	p.Leu80Phe	missense_variant	1/1		NM_002229.3	ENSP00000303315	P1
HOOK2	ENST00000589765.1	n.42-17784G>A		intron_variant, non_coding_transcript_variant		5
HOOK2	ENST00000593143.5	n.259+315G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.238C>T (p.L80F) alteration is located in exon 1 (coding exon 1) of the JUNB gene. This alteration results from a C to T substitution at nucleotide position 238, causing the leucine (L) at amino acid position 80 to be replaced by a phenylalanine (F). 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	0.67
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.84		Gain of methylation at K81 (P = 0.043);
MVP		0.40
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.53
gMVP		0.83

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: rs1418867576; hg19: chr19-12902823;