chr2-25161269-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PVS1_StrongPM2BS1_Supporting
The NM_000939.4(POMC):c.616G>T(p.Glu206Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,611,826 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E206E) has been classified as Likely benign.
Frequency
Consequence
NM_000939.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POMC | NM_000939.4 | c.616G>T | p.Glu206Ter | stop_gained | 3/3 | ENST00000395826.7 | |
POMC | NM_001035256.3 | c.616G>T | p.Glu206Ter | stop_gained | 4/4 | ||
POMC | NM_001319204.2 | c.616G>T | p.Glu206Ter | stop_gained | 4/4 | ||
POMC | NM_001319205.2 | c.616G>T | p.Glu206Ter | stop_gained | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POMC | ENST00000395826.7 | c.616G>T | p.Glu206Ter | stop_gained | 3/3 | 2 | NM_000939.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000382 AC: 58AN: 152022Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000412 AC: 101AN: 245020Hom.: 0 AF XY: 0.000353 AC XY: 47AN XY: 133230
GnomAD4 exome AF: 0.000345 AC: 504AN: 1459684Hom.: 0 Cov.: 32 AF XY: 0.000347 AC XY: 252AN XY: 726000
GnomAD4 genome ? AF: 0.000381 AC: 58AN: 152142Hom.: 1 Cov.: 33 AF XY: 0.000403 AC XY: 30AN XY: 74370
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change creates a premature translational stop signal (p.Glu206*) in the POMC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 62 amino acid(s) of the POMC protein. This variant is present in population databases (rs202127120, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with obesity, in cis with a nearby in-frame insertion (PMID: 9768693, 29970488, 35574020). This variant is also known as Glu-180-Stop. ClinVar contains an entry for this variant (Variation ID: 381722). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 18, 2017 | The E206X variant in the POMC gene has been reported previously according to alternate nomeclature, in cis with an in-frame duplication variant (c.599_604dupGGGCCC) and in trans with a missense variant (E214G), in a German adolescent female with obesity (Hinney et al., 1998). This variant causes the loss of the last 62 amino acid residues and is predicted to cause loss of normal protein function through protein truncation. The E206X variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, we interpret E206X as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at