rs145463534

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1594A>G (p.Ser532Gly) variant in the SHOC2 gene is 1.147% (138/10402) of African 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/CA293486/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.0039 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 1 hom. )

Consequence

SHOC2
NM_007373.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:10

Conservation

PhyloP100: 6.23

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

Noonan syndrome-like disorder with loose anagen hair
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Noonan syndrome-like disorder with loose anagen hair 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, PanelApp Australia
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SHOC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007373.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHOC2	NM_007373.4	MANE Select	c.1594A>G	p.Ser532Gly	missense	Exon 9 of 9	NP_031399.2
SHOC2	NM_001324336.2		c.1594A>G	p.Ser532Gly	missense	Exon 9 of 9	NP_001311265.1	Q9UQ13-1
SHOC2	NM_001324337.2		c.1594A>G	p.Ser532Gly	missense	Exon 10 of 10	NP_001311266.1	Q9UQ13-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHOC2	ENST00000369452.9	TSL:1 MANE Select	c.1594A>G	p.Ser532Gly	missense	Exon 9 of 9	ENSP00000358464.5	Q9UQ13-1
SHOC2	ENST00000685059.1		c.1594A>G	p.Ser532Gly	missense	Exon 10 of 10	ENSP00000510210.1	Q9UQ13-1
SHOC2	ENST00000688928.1		c.1594A>G	p.Ser532Gly	missense	Exon 9 of 9	ENSP00000509273.1	Q9UQ13-1

Frequencies

GnomAD3 genomes

AF:

0.00390

AC:

594

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0139

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000983

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:

0.00

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000899

AC:

226

AN:

251448

AF XY:

0.000581

show subpopulations

Gnomad AFR exome

AF:

0.0126

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000356

AC:

520

AN:

1461798

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

218

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0128

AC:

428

AN:

33474

American (AMR)

AF:

0.000648

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1111942

Other (OTH)

AF:

0.000629

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

107

134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00393

AC:

598

AN:

152282

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

291

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0139

AC:

579

AN:

41566

American (AMR)

AF:

0.000981

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000919

Hom.:

Bravo

AF:

0.00438

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00119

AC:

145

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Noonan syndrome-like disorder with loose anagen hair 1 (2)

RASopathy (2)

Cardiovascular phenotype (1)

Noonan syndrome and Noonan-related syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Benign

0.14

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.33

MutationAssessor

Benign

0.86

PhyloP100

6.2

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.6

REVEL

Benign

0.12

Sift

Benign

0.13

Sift4G

Benign

0.24

Polyphen

0.66

Vest4

0.14

MVP

0.70

MPC

0.71

ClinPred

0.066

GERP RS

1.4

Varity_R

0.13

gMVP

0.46

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over