rs34081996

Variant names:

• chr10-110964815-C-T
• rs34081996
• NM_007373.4:c.457C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.457C>T (p.Leu153=) variant in the SHOC2 gene is 1.574% (1104/66696) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA333154/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.013 (15 hom., cov: 32)
  • Exomes 𝑓: 0.018 (246 hom.)
• Consequence: SHOC2 NM_007373.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:10
• Conservation: PhyloP100: 2.26

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOC2	NM_007373.4	c.457C>T	p.Leu153Leu	synonymous_variant	Exon 2 of 9	ENST00000369452.9	NP_031399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOC2	ENST00000369452.9	c.457C>T	p.Leu153Leu	synonymous_variant	Exon 2 of 9	1	NM_007373.4	ENSP00000358464.5

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1915 AN: 152166 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0310

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0129 AC: 3233 AN: 250852 Hom.: 32 AF XY: 0.0133 AC XY: 1802 AN XY: 135600

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.00686

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00418

Gnomad FIN exome AF: 0.0297

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0151

GnomAD4 exome AF: 0.0177 AC: 25818 AN: 1461796 Hom.: 246 Cov.: 32 AF XY: 0.0173 AC XY: 12549 AN XY: 727214

Gnomad4 AFR exome AF: 0.00302

Gnomad4 AMR exome AF: 0.00745

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00415

Gnomad4 FIN exome AF: 0.0286

Gnomad4 NFE exome AF: 0.0200

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0126 AC: 1915 AN: 152284 Hom.: 15 Cov.: 32 AF XY: 0.0127 AC XY: 943 AN XY: 74474

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0310

Gnomad4 NFE AF: 0.0192

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0156 Hom.: 13

Bravo AF: 0.0105

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0187

EpiControl AF: 0.0196

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Jan 24, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome-like disorder with loose anagen hair 1 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SHOC2: BP4, BP7, BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

RASopathy Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The filtering allele frequency of the c.457C>T (p.Leu153=) variant in the SHOC2 gene is 1.574% (1104/66696) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) -

Cardiovascular phenotype Benign:1

Jun 23, 2020

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Noonan syndrome and Noonan-related syndrome Benign:1

Mar 30, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.5
DANN	Benign	0.41

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

Other links and lift over

dbSNP: rs34081996; hg19: chr10-112724573;