NM_007373.4:c.1540+8C>T

Variant names:

• chr10-111009838-C-T
• rs771283010
• NM_007373.4:c.1540+8C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1540+8C>T variant in the SHOC2 gene is 0.0374% (34/66702) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA5689792/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.00089 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (4 hom.)
• Consequence: SHOC2 NM_007373.4 splice_region, intron
• Scores: Splicing: ADA: 0.01088
• Clinical Significance: Likely benign reviewed by expert panel B:2
• Conservation: PhyloP100: 1.01
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: 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.1540+8C>T		splice_region intron	N/A	NP_031399.2
	SHOC2	NM_001324336.2		c.1540+8C>T		splice_region intron	N/A	NP_001311265.1	Q9UQ13-1
	SHOC2	NM_001324337.2		c.1540+8C>T		splice_region intron	N/A	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.1540+8C>T		splice_region intron	N/A	ENSP00000358464.5	Q9UQ13-1
	SHOC2	ENST00000692776.1		c.1548C>T	p.Asn516Asn	synonymous	Exon 8 of 8	ENSP00000508524.1	A0A8I5KUD9
	SHOC2	ENST00000685059.1		c.1540+8C>T		splice_region intron	N/A	ENSP00000510210.1	Q9UQ13-1

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152148 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00121 AC: 303 AN: 251254 AF XY: 0.00112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000508 AC: 630 AN: 1239424 Hom.: 4 Cov.: 19 AF XY: 0.000491 AC XY: 308 AN XY: 627898

African (AFR) AF: 0.00 AC: 0 AN: 29084

American (AMR) AF: 0.00 AC: 0 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24754

East Asian (EAS) AF: 0.00 AC: 0 AN: 38658

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81780

European-Finnish (FIN) AF: 0.0108 AC: 578 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5308

European-Non Finnish (NFE) AF: 0.0000363 AC: 33 AN: 909004

Other (OTH) AF: 0.000339 AC: 18 AN: 53088

GnomAD4 genome AF: 0.000887 AC: 135 AN: 152148 Hom.: 2 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0117 AC: 124 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68022

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	RASopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	10
DANN	Benign	0.76
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.18
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: rs771283010; hg19: chr10-112769596;