rs730881016
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1
The NM_007373.4(SHOC2):c.973-5del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00533 in 1,579,980 control chromosomes in the GnomAD database, including 418 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0032 ( 26 hom., cov: 32)
Exomes 𝑓: 0.0056 ( 392 hom. )
Consequence
SHOC2
NM_007373.4 splice_polypyrimidine_tract, intron
NM_007373.4 splice_polypyrimidine_tract, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0430
Genes affected
SHOC2 (HGNC:15454): (SHOC2 leucine rich repeat scaffold protein) This gene encodes a protein that consists almost entirely of leucine-rich repeats, a domain implicated in protein-protein interactions. The protein may function as a scaffold linking RAS to downstream signal transducers in the RAS/ERK MAP kinase signaling cascade. Mutations in this gene have been associated with Noonan-like syndrome with loose anagen hair. [provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP6
?
Variant 10-111004593-AT-A is Benign according to our data. Variant chr10-111004593-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 181524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-111004593-AT-A is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0856 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SHOC2 | NM_007373.4 | c.973-5del | splice_polypyrimidine_tract_variant, intron_variant | ENST00000369452.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SHOC2 | ENST00000369452.9 | c.973-5del | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_007373.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00319 AC: 484AN: 151822Hom.: 26 Cov.: 32
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GnomAD3 exomes AF: 0.0113 AC: 2808AN: 249088Hom.: 156 AF XY: 0.0154 AC XY: 2081AN XY: 134824
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GnomAD4 exome AF: 0.00556 AC: 7942AN: 1428042Hom.: 392 Cov.: 28 AF XY: 0.00805 AC XY: 5732AN XY: 712480
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GnomAD4 genome ? AF: 0.00318 AC: 483AN: 151938Hom.: 26 Cov.: 32 AF XY: 0.00478 AC XY: 355AN XY: 74294
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 09, 2019 | Variant summary: SHOC2 c.973-5delT alters a non-conserved 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 0.011 in 249088 control chromosomes, predominantly at a frequency of 0.089 within the South Asian subpopulation in the gnomAD database, including 156 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3560-folds over the estimated maximal expected allele frequency for a pathogenic variant in SHOC2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.973-5delT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
RASopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2014 | The variant is found in NOONAN panel(s). - |
Noonan syndrome-like disorder with loose anagen hair 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2021 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Noonan syndrome and Noonan-related syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | May 21, 2021 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at