Genetic Variant SHOC2:p.Ser2Gly (chr10-110964362-AGT-GGC) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM2

The NM_007373.4(SHOC2):c.4_6delAGTinsGGC (p.Ser2Gly) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.11). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S2T: Uncertain_significance (ClinVar VariationId 2265459, 1 star) The same amino acid change has been reported as oncogenic or likely oncogenic in a clinical somatic variant database. This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: not found (cov: 32)

Consequence

SHOC2
NM_007373.4 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.11

Publications

0 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: PanelApp Australia, Genomics England PanelApp, 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

SHOC2 links:

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new If you want to explore the variant's impact on the transcript NM_007373.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

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

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 10 points.

Show applied only (2)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 3 stars).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
SHOC2 NM_007373.4	MANE Select	c.4_6delAGTinsGGC p.Ser2Gly	missense	N/A	Prot: NP_031399.2
SHOC2 NM_001324336.2		c.4_6delAGTinsGGC p.Ser2Gly	missense	N/A	Prot: NP_001311265.1 UniProt: Q9UQ13-1
SHOC2 NM_001324337.2		c.4_6delAGTinsGGC p.Ser2Gly	missense	N/A	Prot: NP_001311266.1 UniProt: Q9UQ13-1

SHOC2 NM_007373.4

MANE Select

HGVSc / HGVSpc.4_6delAGTinsGGCp.Ser2Gly

Exon rankN/A

missense

Prot: NP_031399.2

SHOC2 NM_001324336.2

HGVSc / HGVSpc.4_6delAGTinsGGCp.Ser2Gly

Exon rankN/A

missense

Prot: NP_001311265.1UniProt: Q9UQ13-1

SHOC2 NM_001324337.2

HGVSc / HGVSpc.4_6delAGTinsGGCp.Ser2Gly

Exon rankN/A

missense

Prot: NP_001311266.1UniProt: Q9UQ13-1

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
SHOC2 ENST00000369452.9	TSL:1MANE Select	c.4_6delAGTinsGGC p.Ser2Gly	missense	N/A	Prot: ENSP00000358464.5 UniProt: Q9UQ13-1
SHOC2 ENST00000685059.1		c.4_6delAGTinsGGC p.Ser2Gly	missense	N/A	Prot: ENSP00000510210.1 UniProt: Q9UQ13-1
SHOC2 ENST00000688928.1		c.4_6delAGTinsGGC p.Ser2Gly	missense	N/A	Prot: ENSP00000509273.1 UniProt: Q9UQ13-1

SHOC2 ENST00000369452.9

TSL:1MANE Select

HGVSc / HGVSpc.4_6delAGTinsGGCp.Ser2Gly

Exon rankN/A

missense

Prot: ENSP00000358464.5UniProt: Q9UQ13-1

SHOC2 ENST00000685059.1

HGVSc / HGVSpc.4_6delAGTinsGGCp.Ser2Gly

Exon rankN/A

missense

Prot: ENSP00000510210.1UniProt: Q9UQ13-1

SHOC2 ENST00000688928.1

HGVSc / HGVSpc.4_6delAGTinsGGCp.Ser2Gly

Exon rankN/A

missense

Prot: ENSP00000509273.1UniProt: Q9UQ13-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.1

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence