Variant 10-110919546-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.260

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	UniProt
SHOC2	NM_001324336.2 linkuse as main transcript	c.-235+105T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	Appris	UniProt
SHOC2	ENST00000688928.1 linkuse as main transcript	c.-235+105T>G	intron_variant		P1	Q9UQ13-1
SHOC2	ENST00000451838.2 linkuse as main transcript		upstream_gene_variant	2
SHOC2	ENST00000689300.1 linkuse as main transcript		upstream_gene_variant		P1	Q9UQ13-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

3868

AN:

15810

Hom.:

Cov.:

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:

AN:

15150

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

AN XY:

7616

show subpopulations

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.:

Cov.:

AF XY:

0.234

AC XY:

1665

AN XY:

7124

show subpopulations

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

LINK: link

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

DANN

Benign

0.73

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over