chr10-110964358-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2
The NM_007373.4(SHOC2):c.-1C>T variant causes a 5 prime UTR change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SHOC2
NM_007373.4 5_prime_UTR
NM_007373.4 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 5.82
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 Likely_benign. Variant got -4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.3).
BS2
?
High AC in GnomAdExome at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SHOC2 | NM_007373.4 | c.-1C>T | 5_prime_UTR_variant | 2/9 | ENST00000369452.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SHOC2 | ENST00000369452.9 | c.-1C>T | 5_prime_UTR_variant | 2/9 | 1 | NM_007373.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000283 AC: 7AN: 247074Hom.: 0 AF XY: 0.0000372 AC XY: 5AN XY: 134252
GnomAD3 exomes
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000479 AC: 7AN: 1460672Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726626
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome ? Cov.: 32
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Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 07, 2012 | The c.-1 C>T variant in the SHOC2 gene is located 1 nucleotide before the ATG translation start signal. This nucleotide position is conserved across species and substitution of this nucleotide may disrupt the Kozak sequence. The NHLBI ESP Exome Variant Server reports that the c.-1 C>T substitution was not observed in approximately 5000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. It is unknown if the c.-1 C>T variant would have a deleterious affect, but to date, haploinsufficiency is not a reported mechanism for SHOC2- related disorders. The variant is found in NOONAN panel(s). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 03, 2013 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 23, 2020 | The c.-1C>T variant is located in the 5' untranslated region (5’ UTR) of the SHOC2 gene. This variant results from a C to T substitution 1 bases upstream from the first translated codon. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
RASopathy Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | The c.-1C>T variant in SHOC2 has been identified in 2 independent occurrences in patients with a clinical features of a RASopathy (PS4 not met; GeneDx, EGL internal data GTR Lab ID's: 26957, 500060 ClinVar SCV000209050.9, SCV000113449.7). The allele frequency of the c.-1T>C variant in the SHOC2 gene is 0.01% (1/10164) of Latino chromosomes by the Exome Aggregation Consortium (PM2 not met; http://exac.broadinstitute.org). In summary, the clinical significance of the c.-1C>T variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): NONE. - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at