chr1-154572164-G-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000748.3(CHRNB2):c.1338+3G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000521 in 1,536,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000748.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHRNB2 | NM_000748.3 | c.1338+3G>T | splice_region_variant, intron_variant | Intron 5 of 5 | ENST00000368476.4 | NP_000739.1 | ||
CHRNB2 | XM_017000180.3 | c.828+3G>T | splice_region_variant, intron_variant | Intron 2 of 2 | XP_016855669.1 | |||
CHRNB2 | XR_001736952.3 | n.1605+3G>T | splice_region_variant, intron_variant | Intron 5 of 6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHRNB2 | ENST00000368476.4 | c.1338+3G>T | splice_region_variant, intron_variant | Intron 5 of 5 | 1 | NM_000748.3 | ENSP00000357461.3 | |||
CHRNB2 | ENST00000637900.1 | c.1344+3G>T | splice_region_variant, intron_variant | Intron 5 of 5 | 5 | ENSP00000490474.1 | ||||
CHRNB2 | ENST00000636034.1 | n.1338+3G>T | splice_region_variant, intron_variant | Intron 5 of 8 | 5 | ENSP00000489703.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152256Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000151 AC: 2AN: 132374Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 72214
GnomAD4 exome AF: 0.00000433 AC: 6AN: 1384574Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 683344
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74384
ClinVar
Submissions by phenotype
Autosomal dominant nocturnal frontal lobe epilepsy 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Autosomal dominant nocturnal frontal lobe epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 31, 2024 | This sequence change falls in intron 5 of the CHRNB2 gene. It does not directly change the encoded amino acid sequence of the CHRNB2 protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CHRNB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 430409). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 29, 2020 | The c.1338+3G>T intronic alteration consists of a G to T substitution 3 nucleotides after exon 5 (coding exon 5) of the CHRNB2 gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2017 | A variant of uncertain significance has been identified in the CHRNB2 gene. The c.1338+3 G>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1338+3 G>T variant is not observed in large population cohorts; however, limited data are available (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.1338+3 G>T may damage or destroy the natural splice donor site in intron 5 and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Additionally, to our knowledge, splice variants have not been reported in the CHRNB2 gene (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at