chr10-111011593-AT-A

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

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.46
Variant links:
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

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SHOC2NM_007373.4 linkc.1541-7delT splice_region_variant, intron_variant ENST00000369452.9 NP_031399.2 Q9UQ13-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SHOC2ENST00000369452.9 linkc.1541-16delT intron_variant 1 NM_007373.4 ENSP00000358464.5 Q9UQ13-1

Frequencies

GnomAD3 genomes
AF:
0.00604
AC:
911
AN:
150756
Hom.:
9
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00107
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00503
Gnomad ASJ
AF:
0.000869
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0290
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00705
Gnomad OTH
AF:
0.00530
GnomAD3 exomes
AF:
0.00704
AC:
1575
AN:
223736
Hom.:
12
AF XY:
0.00700
AC XY:
849
AN XY:
121300
show subpopulations
Gnomad AFR exome
AF:
0.00145
Gnomad AMR exome
AF:
0.00185
Gnomad ASJ exome
AF:
0.000662
Gnomad EAS exome
AF:
0.000356
Gnomad SAS exome
AF:
0.000221
Gnomad FIN exome
AF:
0.0337
Gnomad NFE exome
AF:
0.00836
Gnomad OTH exome
AF:
0.00714
GnomAD4 exome
AF:
0.00741
AC:
10251
AN:
1382662
Hom.:
54
Cov.:
28
AF XY:
0.00705
AC XY:
4872
AN XY:
690804
show subpopulations
Gnomad4 AFR exome
AF:
0.00155
Gnomad4 AMR exome
AF:
0.00194
Gnomad4 ASJ exome
AF:
0.000556
Gnomad4 EAS exome
AF:
0.0000517
Gnomad4 SAS exome
AF:
0.000190
Gnomad4 FIN exome
AF:
0.0278
Gnomad4 NFE exome
AF:
0.00794
Gnomad4 OTH exome
AF:
0.00652
GnomAD4 genome
AF:
0.00604
AC:
912
AN:
150874
Hom.:
9
Cov.:
32
AF XY:
0.00695
AC XY:
512
AN XY:
73694
show subpopulations
Gnomad4 AFR
AF:
0.00107
Gnomad4 AMR
AF:
0.00503
Gnomad4 ASJ
AF:
0.000869
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0290
Gnomad4 NFE
AF:
0.00706
Gnomad4 OTH
AF:
0.00525
Alfa
AF:
0.00354
Hom.:
0
Bravo
AF:
0.00446

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 providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 01, 2019Variant 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 providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingGeneDxJan 09, 2019- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2022SHOC2: BS1, BS2 -
Noonan syndrome-like disorder with loose anagen hair 1 Benign:1
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 09, 2023- -
SHOC2-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 08, 2019This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Noonan syndrome and Noonan-related syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMay 07, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs371544139; hg19: chr10-112771351; API