chr10-110964368-A-C
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP5
This summary comes from the ClinGen Evidence Repository: The c.10A>C variant in SHOC2 has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM GTR Lab ID: 26957, 21766 internal data; ClinVar SCV000209046.7, SCV000062455.5). The filtering allele frequency of the c.10A>C (p.Ser4Arg) variant is 0.356% for Latino chromosomes by the Exome Aggregation Consortium (49/10712 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA136657/MONDO:0021060/004
Frequency
Consequence
NM_007373.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SHOC2 | NM_007373.4 | c.10A>C | p.Ser4Arg | missense_variant | 2/9 | ENST00000369452.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SHOC2 | ENST00000369452.9 | c.10A>C | p.Ser4Arg | missense_variant | 2/9 | 1 | NM_007373.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000420 AC: 104AN: 247788Hom.: 0 AF XY: 0.000312 AC XY: 42AN XY: 134572
GnomAD4 exome AF: 0.0000821 AC: 120AN: 1460864Hom.: 0 Cov.: 31 AF XY: 0.0000688 AC XY: 50AN XY: 726780
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74354
ClinVar
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 13, 2015 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 24, 2019 | Variant summary: SHOC2 c.10A>C (p.Ser4Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 247788 control chromosomes, predominantly at a frequency of 0.003 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 120 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 a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.10A>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a pathogenic variant has been reported (PTPN11 c.5C>T, p.Thr2Ile; LabCorp), providing supporting evidence for a benign role. Three ClinVar submitters including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant once as likely benign and twice as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Noonan syndrome-like disorder with loose anagen hair 1 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 28, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 04, 2020 | - - |
RASopathy Benign:2
Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | The c.10A>C variant in SHOC2 has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM GTR Lab ID: 26957, 21766 internal data; ClinVar SCV000209046.7, SCV000062455.5). The filtering allele frequency of the c.10A>C (p.Ser4Arg) variant is 0.356% for Latino chromosomes by the Exome Aggregation Consortium (49/10712 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2017 | 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. - |
SHOC2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 22, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at