Variant rs34081996 details in Genebe, Genetics Data Aggregator

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

Scores

Clinical Significance

Benign reviewed by expert panel B:10

Conservation

PhyloP100: 2.26

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]

SHOC2 links:

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ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
SHOC2	NM_007373.4 linkuse as main transcript	c.457C>T	p.Leu153=	synonymous_variant	2/9	ENST00000369452.9	NP_031399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHOC2	ENST00000369452.9 linkuse as main transcript	c.457C>T	p.Leu153=	synonymous_variant	2/9	1	NM_007373.4	ENSP00000358464	P1	Q9UQ13-1

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1915

AN:

152166

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0133

AC XY:

1802

AN XY:

135600

show subpopulations

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.:

AF XY:

0.0173

AC XY:

12549

AN XY:

727214

show subpopulations

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.:

Cov.:

AF XY:

0.0127

AC XY:

943

AN XY:

74474

show subpopulations

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.:

Bravo

AF:

0.0105

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0187

EpiControl

AF:

0.0196

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Noonan syndrome-like disorder with loose anagen hair 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	SHOC2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

RASopathy

Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 18, 2017	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) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2020

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 30, 2021

- -

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over