10-110919546-T-G

Position:

• chr10-110919546-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001324336.2(SHOC2):​c.-235+105T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.24 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00086 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHOC2 NM_001324336.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.260

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000858 (13/15150) while in subpopulation NFE AF= 0.000882 (8/9070). AF 95% confidence interval is 0.000438. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHOC2	NM_001324336.2	c.-235+105T>G		intron_variant			NP_001311265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHOC2	ENST00000688928.1	c.-235+105T>G		intron_variant				ENSP00000509273	P1
SHOC2	ENST00000451838.2			upstream_gene_variant		2		ENSP00000408275
SHOC2	ENST00000689300.1			upstream_gene_variant				ENSP00000510639	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 3868 AN: 15810 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.238

GnomAD4 exome AF: 0.000858 AC: 13 AN: 15150 Hom.: 0 Cov.: 0 AF XY: 0.000525 AC XY: 4 AN XY: 7616

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00166

Gnomad4 NFE exome AF: 0.000882

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.245 AC: 3877 AN: 15844 Hom.: 0 Cov.: 0 AF XY: 0.234 AC XY: 1665 AN XY: 7124

Gnomad4 AFR AF: 0.235

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.285

Gnomad4 EAS AF: 0.195

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.223

Gnomad4 NFE AF: 0.264

Gnomad4 OTH AF: 0.238

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Noonan syndrome-like disorder with loose anagen hair 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.73

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1203298501; hg19: chr10-112679304;