rs376859485
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_007373.4(SHOC2):c.1162-16T>G 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 0.0000682 in 1,613,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00047 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
SHOC2
NM_007373.4 splice_polypyrimidine_tract, intron
NM_007373.4 splice_polypyrimidine_tract, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.525
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 -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.66).
BP6
?
Variant 10-111007515-T-G is Benign according to our data. Variant chr10-111007515-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 260160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000466 (71/152330) while in subpopulation AFR AF= 0.00159 (66/41586). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 71 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SHOC2 | NM_007373.4 | c.1162-16T>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000369452.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SHOC2 | ENST00000369452.9 | c.1162-16T>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_007373.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000466 AC: 71AN: 152212Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000955 AC: 24AN: 251340Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135856
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461014Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 726834
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GnomAD4 genome ? AF: 0.000466 AC: 71AN: 152330Hom.: 0 Cov.: 31 AF XY: 0.000564 AC XY: 42AN XY: 74502
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
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.1162-16T>G 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 9.5e-05 in 251340 control chromosomes, predominantly at a frequency of 0.0013 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 52 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 African or African-American origin. A ClinVar submitter (submission after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
RASopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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