10-110964358-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_007373.4(SHOC2):c.-1C>T variant causes a 5 prime UTR change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHOC2 NM_007373.4 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 5.82

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BS2: High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOC2	NM_007373.4	c.-1C>T		5_prime_UTR_variant	2/9	ENST00000369452.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOC2	ENST00000369452.9	c.-1C>T		5_prime_UTR_variant	2/9	1	NM_007373.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000283 AC: 7 AN: 247074 Hom.: 0 AF XY: 0.0000372 AC XY: 5 AN XY: 134252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000479 AC: 7 AN: 1460672 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2012	The c.-1 C>T variant in the SHOC2 gene is located 1 nucleotide before the ATG translation start signal. This nucleotide position is conserved across species and substitution of this nucleotide may disrupt the Kozak sequence. The NHLBI ESP Exome Variant Server reports that the c.-1 C>T substitution was not observed in approximately 5000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. It is unknown if the c.-1 C>T variant would have a deleterious affect, but to date, haploinsufficiency is not a reported mechanism for SHOC2- related disorders. The variant is found in NOONAN panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 03, 2013	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2020

The c.-1C>T variant is located in the 5' untranslated region (5’ UTR) of the SHOC2 gene. This variant results from a C to T substitution 1 bases upstream from the first translated codon. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

RASopathy Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Apr 03, 2017

The c.-1C>T variant in SHOC2 has been identified in 2 independent occurrences in patients with a clinical features of a RASopathy (PS4 not met; GeneDx, EGL internal data GTR Lab ID's: 26957, 500060 ClinVar SCV000209050.9, SCV000113449.7). The allele frequency of the c.-1T>C variant in the SHOC2 gene is 0.01% (1/10164) of Latino chromosomes by the Exome Aggregation Consortium (PM2 not met; http://exac.broadinstitute.org). In summary, the clinical significance of the c.-1C>T variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): NONE. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
Cadd	Benign	20
Dann	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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

Publications

LitVar

Other links and lift over

dbSNP: rs398124252; hg19: chr10-112724116;