rs34081996

Variant names:

• chr10-110964815-C-T
• rs34081996
• NM_007373.4:c.457C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.457C>T (p.Leu153=) variant in the SHOC2 gene is 1.574% (1104/66696) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA333154/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.013 (15 hom., cov: 32)
  • Exomes 𝑓: 0.018 (246 hom.)
• Consequence: SHOC2 NM_007373.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:10
• Conservation: PhyloP100: 2.26
• Publications: 5 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: Benign. The variant received -8 ACMG points.

• BA1: 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.457C>T	p.Leu153Leu	synonymous	Exon 2 of 9	NP_031399.2
	SHOC2	NM_001324336.2		c.457C>T	p.Leu153Leu	synonymous	Exon 2 of 9	NP_001311265.1	Q9UQ13-1
	SHOC2	NM_001324337.2		c.457C>T	p.Leu153Leu	synonymous	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.457C>T	p.Leu153Leu	synonymous	Exon 2 of 9	ENSP00000358464.5	Q9UQ13-1
	SHOC2	ENST00000685059.1		c.457C>T	p.Leu153Leu	synonymous	Exon 3 of 10	ENSP00000510210.1	Q9UQ13-1
	SHOC2	ENST00000688928.1		c.457C>T	p.Leu153Leu	synonymous	Exon 2 of 9	ENSP00000509273.1	Q9UQ13-1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1915 AN: 152166 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0310

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0129 AC: 3233 AN: 250852 AF XY: 0.0133

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.00686

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0297

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0151

GnomAD4 exome AF: 0.0177 AC: 25818 AN: 1461796 Hom.: 246 Cov.: 32 AF XY: 0.0173 AC XY: 12549 AN XY: 727214

African (AFR) AF: 0.00302 AC: 101 AN: 33476

American (AMR) AF: 0.00745 AC: 333 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00352 AC: 92 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00415 AC: 358 AN: 86258

European-Finnish (FIN) AF: 0.0286 AC: 1526 AN: 53420

Middle Eastern (MID) AF: 0.0173 AC: 100 AN: 5768

European-Non Finnish (NFE) AF: 0.0200 AC: 22279 AN: 1111936

Other (OTH) AF: 0.0170 AC: 1028 AN: 60386

GnomAD4 genome AF: 0.0126 AC: 1915 AN: 152284 Hom.: 15 Cov.: 32 AF XY: 0.0127 AC XY: 943 AN XY: 74474

African (AFR) AF: 0.00267 AC: 111 AN: 41562

American (AMR) AF: 0.00719 AC: 110 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4828

European-Finnish (FIN) AF: 0.0310 AC: 329 AN: 10604

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0192 AC: 1303 AN: 68018

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.0156 Hom.: 13

Bravo AF: 0.0105

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0187

EpiControl AF: 0.0196

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Noonan syndrome-like disorder with loose anagen hair 1 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.5
DANN	Benign	0.41
PhyloP100		2.3
Mutation Taster		=98/2	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: rs34081996; hg19: chr10-112724573;