chr14-50118856-C-CAA
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1
The NM_006939.4(SOS2):c.3490-5_3490-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0512 in 1,134,490 control chromosomes in the GnomAD database, including 378 homozygotes. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_006939.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SOS2 | ENST00000216373.10 | c.3490-4_3490-3insTT | splice_region_variant, intron_variant | Intron 22 of 22 | 1 | NM_006939.4 | ENSP00000216373.5 | |||
SOS2 | ENST00000543680.5 | c.3391-4_3391-3insTT | splice_region_variant, intron_variant | Intron 21 of 21 | 1 | ENSP00000445328.1 |
Frequencies
GnomAD3 genomes AF: 0.0303 AC: 4322AN: 142640Hom.: 82 Cov.: 0
GnomAD3 exomes AF: 0.0382 AC: 3970AN: 103896Hom.: 41 AF XY: 0.0403 AC XY: 2289AN XY: 56850
GnomAD4 exome AF: 0.0542 AC: 53736AN: 991764Hom.: 296 Cov.: 24 AF XY: 0.0539 AC XY: 25812AN XY: 478790
GnomAD4 genome AF: 0.0303 AC: 4318AN: 142726Hom.: 82 Cov.: 0 AF XY: 0.0302 AC XY: 2083AN XY: 68992
ClinVar
Submissions by phenotype
Noonan syndrome 9 Benign:3
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not specified Benign:2
Variant summary: SOS2 c.3490-5_3490-4dupTT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.038 in 103896 control chromosomes in the gnomAD database (exomes dataset), including 41 homozygotes. The observed variant frequency is approximately 15000 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3490-5_3490-4dupTT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cited the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
SOS2-related disorder Benign:1
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Noonan syndrome and Noonan-related syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at