10-110964968-A-G

Position:

chr10-110964968-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS4BS2BP4

This summary comes from the ClinGen Evidence Repository: The c.610A>G (p.Ile204Val) variant in SHOC2 is present in 0.01241% (16/128978) of non-Finnish European alleles in gnomAD. This variant was observed in 3 unaffected individuals as well as several individuals with varying clinical presentations lacking clear associations with a RASopathy (BS2; Invitae internal data, SCV000289856.3; Institut Universitaire d'Hématologie internal data). It was absent from the symptomatic sister of 1 proband with Noonan syndrome who carried this variant (BS4; Institut Universitaire d'Hématologie internal data). Computational analysis and splice site predictors suggest that this variant does not impact the protein (BP4). In summary, the p.Ile204Val variant meets criteria to be classified as benign for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP Criteria applied (PMID:29493581): BS2, BS4, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA5689600/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

SHOC2
NM_007373.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 7.51

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

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

BS2

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

BS4

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.610A>G	p.Ile204Val	missense_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.610A>G	p.Ile204Val	missense_variant	2/9	1	NM_007373.4	ENSP00000358464	P1	Q9UQ13-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000678

AC:

AN:

250862

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000746

AC:

109

AN:

1461426

Hom.:

Cov.:

AF XY:

0.0000757

AC XY:

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000926

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2017	The I204V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is observed in 2/10232 (0.02%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). I204V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 02, 2016	- -

RASopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 204 of the SHOC2 protein (p.Ile204Val). This variant is present in population databases (rs200015085, gnomAD 0.01%). This missense change has been observed in individual(s) with sudden infant death syndrome (PMID: 28074886). ClinVar contains an entry for this variant (Variation ID: 240838). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SHOC2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 07, 2020

Variant summary: SHOC2 c.610A>G (p.Ile204Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250862 control chromosomes (gnomAD). The observed variant frequency is approximately 2.7 fold 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. c.610A>G has been reported in the literature in an individual affected with SIDS (Naubauer_2017). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, three classified the variant as VUS while one classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Noonan syndrome-like disorder with loose anagen hair 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;.;T

Eigen

Benign

-0.014

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.7

L;L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.84

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.20

T;T;T

Polyphen

0.012

B;B;.

Vest4

0.27

MVP

0.41

MPC

0.43

ClinPred

0.11

GERP RS

4.5

Varity_R

0.17

gMVP

0.52

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