chr10-110964363-G-C

Variant names:

• chr10-110964363-G-C
• NM_007373.4:c.5G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_007373.4(SHOC2):​c.5G>C​(p.Ser2Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S2G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHOC2 NM_007373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.11
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-110964362-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6821.Status of the report is reviewed_by_expert_panel, 3 stars.

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.5G>C	p.Ser2Thr	missense	Exon 2 of 9	NP_031399.2
	SHOC2	NM_001324336.2		c.5G>C	p.Ser2Thr	missense	Exon 2 of 9	NP_001311265.1	Q9UQ13-1
	SHOC2	NM_001324337.2		c.5G>C	p.Ser2Thr	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.5G>C	p.Ser2Thr	missense	Exon 2 of 9	ENSP00000358464.5	Q9UQ13-1
	SHOC2	ENST00000685059.1		c.5G>C	p.Ser2Thr	missense	Exon 3 of 10	ENSP00000510210.1	Q9UQ13-1
	SHOC2	ENST00000688928.1		c.5G>C	p.Ser2Thr	missense	Exon 2 of 9	ENSP00000509273.1	Q9UQ13-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.9	M
PhyloP100		9.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.64	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.20	T
Polyphen		0.92	P
Vest4		0.59
MutPred		0.44		Gain of sheet (P = 0.0073)
MVP		0.38
MPC		1.2
ClinPred		0.96	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.55
gMVP		0.021
Mutation Taster		=67/33	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

hg19: chr10-112724121;