rs1060501927

Variant names:

• chr10-111000523-A-G
• rs1060501927
• NM_007373.4:c.950A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007373.4(SHOC2):​c.950A>G​(p.Asn317Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N317N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHOC2 NM_007373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 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: ClinGen, Orphanet
• Noonan syndrome-like disorder with loose anagen hair 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOC2	NM_007373.4	MANE Select	c.950A>G	p.Asn317Ser	missense	Exon 4 of 9	NP_031399.2
	SHOC2	NM_001324336.2		c.950A>G	p.Asn317Ser	missense	Exon 4 of 9	NP_001311265.1
	SHOC2	NM_001324337.2		c.950A>G	p.Asn317Ser	missense	Exon 5 of 10	NP_001311266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOC2	ENST00000369452.9	TSL:1 MANE Select	c.950A>G	p.Asn317Ser	missense	Exon 4 of 9	ENSP00000358464.5
	SHOC2	ENST00000685059.1		c.950A>G	p.Asn317Ser	missense	Exon 5 of 10	ENSP00000510210.1
	SHOC2	ENST00000688928.1		c.950A>G	p.Asn317Ser	missense	Exon 4 of 9	ENSP00000509273.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.43		Gain of sheet (P = 0.0266)
MVP		0.87
MPC		1.2
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.35
gMVP		0.79
Mutation Taster		=31/69	disease causing

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: rs1060501927; hg19: chr10-112760281;