chr10-111011593-AT-A
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2
The NM_007373.4(SHOC2):c.1541-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00728 in 1,533,536 control chromosomes in the GnomAD database, including 63 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0060 ( 9 hom., cov: 32)
Exomes 𝑓: 0.0074 ( 54 hom. )
Consequence
SHOC2
NM_007373.4 splice_region, intron
NM_007373.4 splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.46
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 -12 ACMG points.
BP6
Variant 10-111011593-AT-A is Benign according to our data. Variant chr10-111011593-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 928786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-111011593-AT-A is described in Lovd as [Benign].
BS2
High AC in GnomAd4 at 912 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00604 AC: 911AN: 150756Hom.: 9 Cov.: 32
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GnomAD3 exomes AF: 0.00704 AC: 1575AN: 223736Hom.: 12 AF XY: 0.00700 AC XY: 849AN XY: 121300
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GnomAD4 exome AF: 0.00741 AC: 10251AN: 1382662Hom.: 54 Cov.: 28 AF XY: 0.00705 AC XY: 4872AN XY: 690804
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GnomAD4 genome AF: 0.00604 AC: 912AN: 150874Hom.: 9 Cov.: 32 AF XY: 0.00695 AC XY: 512AN XY: 73694
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 01, 2019 | Variant summary: SHOC2 c.1541-7delT 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. 4/4 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 0.007 in 223736 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 282 fold of 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 benign. To our knowledge, no occurrence of c.1541-7delT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 09, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | SHOC2: BS1, BS2 - |
Noonan syndrome-like disorder with loose anagen hair 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 09, 2023 | - - |
SHOC2-related disorder Benign:1
Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 08, 2019 | 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). - |
RASopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Noonan syndrome and Noonan-related syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | May 07, 2021 | - - |
Computational scores
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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