15-40217580-G-C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting
The NM_001211.6(BUB1B):c.2763G>C(p.Gln921His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001211.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BUB1B | NM_001211.6 | c.2763G>C | p.Gln921His | missense_variant | Exon 21 of 23 | ENST00000287598.11 | NP_001202.5 | |
BUB1B-PAK6 | NM_001128628.3 | c.-288G>C | 5_prime_UTR_variant | Exon 1 of 11 | NP_001122100.1 | |||
BUB1B-PAK6 | NM_001128629.3 | c.-205G>C | 5_prime_UTR_variant | Exon 1 of 10 | NP_001122101.1 | |||
LOC107984763 | XR_001751506.2 | n.217+21905C>G | intron_variant | Intron 1 of 2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BUB1B | ENST00000287598.11 | c.2763G>C | p.Gln921His | missense_variant | Exon 21 of 23 | 1 | NM_001211.6 | ENSP00000287598.7 | ||
BUB1B | ENST00000412359.7 | c.2805G>C | p.Gln935His | missense_variant | Exon 21 of 23 | 2 | ENSP00000398470.3 |
Frequencies
GnomAD3 genomes AF: 0.000302 AC: 46AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251460Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135916
GnomAD4 exome AF: 0.000205 AC: 299AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.000232 AC XY: 169AN XY: 727234
GnomAD4 genome AF: 0.000302 AC: 46AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22AN XY: 74346
ClinVar
Submissions by phenotype
Mosaic variegated aneuploidy syndrome 1 Pathogenic:1Uncertain:3
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This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 921 of the BUB1B protein (p.Gln921His). This variant is present in population databases (rs28989183, gnomAD 0.04%). This missense change has been observed in individual(s) with mosaic variegated aneuploidy, pancreatic cancer, lung cancer, endometrial cancer, glioblastoma, and melanoma (PMID: 15475955, 18548531, 28767289, 29625052, 36451132). ClinVar contains an entry for this variant (Variation ID: 6762). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect BUB1B function (PMID: 20516114). 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. -
The BUB1B c.2763G>C (p.Gln921His) missense variant has a maximum subpopulation frequency of 0.034% in gnomAD v2.1.1. This variant has been reported in a patient with clinical features of mosaic variegated aneuploidy syndrome including IUGR, microcephaly, cryptochidism, and embryonal rhabdomyosarcoma of the palate (PMID: 15475955). The variant was found to be maternally inherited along with a second BUB1B missense variant; the patient had a paternally inherited truncating variant in BUB1B. This variant has been reported as heterozygous in adults with various cancers including glioblastoma, lung squamous cell carcinoma, skin cutaneous melanoma, and uterine corpus endometrial carcinoma (PMID: 29625052, 36451132). The in silico tool REVEL predicts a benign effect on protein function, and the variant behaved similar to the wild-type in functional studies (PMID: 20516114). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
not provided Uncertain:1Benign:1
Observed in individuals with mosaic variegated aneuploidy and in individuals with pancreatic cancer and breast and/or ovarian cancer (Hanks 2004, Garca-Castillo 2008, Maxwell 2016, Shindo 2017); Published functional studies demonstrate no damaging effect: normal protein levels and functionality (Suijkerbuijk 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29625052, 18548531, 28767289, 27153395, 15475955, 20516114) -
BUB1B: BP4 -
Inborn genetic diseases Uncertain:1
The c.2763G>C (p.Q921H) alteration is located in exon 21 (coding exon 21) of the BUB1B gene. This alteration results from a G to C substitution at nucleotide position 2763, causing the glutamine (Q) at amino acid position 921 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Colorectal cancer;C1850343:Mosaic variegated aneuploidy syndrome 1;C1864389:Premature chromatid separation trait Uncertain:1
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Premature chromatid separation trait Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at