rs267607048

Variant names:

• chr10-110964362-A-G
• rs267607048
• NM_007373.4:c.4A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PP2 PM2 PS2 PS4 PS3

This summary comes from the ClinGen Evidence Repository: The c.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in multiple patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; ClinVar SCV000062456.5, SCV000209051.10, SCV000263045.1 PMID 19684605, 21548061, 23918763, 22528146). The p.Ser2Gly variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data GTR ID's: 506381, 28338; PMID:25563136, 24458587). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID:19684605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SHOC2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS3, PS4, PM2, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA118524/MONDO:0054637/004

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SHOC2 NM_007373.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:47 O:1
• Conservation: PhyloP100: 8.49
• Publications: 87 publications found

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

ACMG classification

Specifications for SHOC2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOC2	NM_007373.4	MANE Select	c.4A>G	p.Ser2Gly	missense	Exon 2 of 9	NP_031399.2
	SHOC2	NM_001324336.2		c.4A>G	p.Ser2Gly	missense	Exon 2 of 9	NP_001311265.1	Q9UQ13-1
	SHOC2	NM_001324337.2		c.4A>G	p.Ser2Gly	missense	Exon 3 of 10	NP_001311266.1	Q9UQ13-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOC2	ENST00000369452.9	TSL:1 MANE Select	c.4A>G	p.Ser2Gly	missense	Exon 2 of 9	ENSP00000358464.5	Q9UQ13-1
	SHOC2	ENST00000685059.1		c.4A>G	p.Ser2Gly	missense	Exon 3 of 10	ENSP00000510210.1	Q9UQ13-1
	SHOC2	ENST00000688928.1		c.4A>G	p.Ser2Gly	missense	Exon 2 of 9	ENSP00000509273.1	Q9UQ13-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460838 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726742

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111492

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00000988 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
25	-	-	Noonan syndrome-like disorder with loose anagen hair 1 (26)
10	-	-	not provided (10)
3	-	-	RASopathy (3)
2	-	-	Noonan syndrome (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Houge-Janssens syndrome 2 (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	Noonan syndrome-like disorder with loose anagen hair (1)
1	-	-	Pectus excavatum;C4478716:Noonan syndrome-like disorder with loose anagen hair 1 (1)
1	-	-	Polycystic kidney disease 4 (1)
1	-	-	SHOC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.9	M
PhyloP100		8.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.60	T
Polyphen		0.92	P
Vest4		0.71
MutPred		0.74		Loss of phosphorylation at S2 (P = 0.0013)
MVP		0.51
MPC		1.2
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.44
gMVP		0.017
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267607048; hg19: chr10-112724120; COSMIC: COSV54624833; COSMIC: COSV54624833;