NM_007373.4:c.11G>A

Variant names:

• chr10-110964369-G-A
• rs1458057852
• NM_007373.4:c.11G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007373.4(SHOC2):​c.11G>A​(p.Ser4Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S4R) has been classified as 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: 4.46
• 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: 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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08272663).

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.11G>A	p.Ser4Asn	missense	Exon 2 of 9	NP_031399.2
	SHOC2	NM_001324336.2		c.11G>A	p.Ser4Asn	missense	Exon 2 of 9	NP_001311265.1	Q9UQ13-1
	SHOC2	NM_001324337.2		c.11G>A	p.Ser4Asn	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.11G>A	p.Ser4Asn	missense	Exon 2 of 9	ENSP00000358464.5	Q9UQ13-1
	SHOC2	ENST00000685059.1		c.11G>A	p.Ser4Asn	missense	Exon 3 of 10	ENSP00000510210.1	Q9UQ13-1
	SHOC2	ENST00000688928.1		c.11G>A	p.Ser4Asn	missense	Exon 2 of 9	ENSP00000509273.1	Q9UQ13-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.069
Sift	Benign	0.31	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.31		Loss of phosphorylation at S4 (P = 9e-04)
MVP		0.20
MPC		0.45
ClinPred		0.50	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.071
gMVP		0.0064
Mutation Taster		=74/26	polymorphism

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: rs1458057852; hg19: chr10-112724127;