rs371544139

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_007373.4(SHOC2):c.1541-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00728 in 1,533,536 control chromosomes in the GnomAD database, including 63 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0074 ( 54 hom. )

Consequence

SHOC2
NM_007373.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.46

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:

SHOC2 (HGNC:):

SHOC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 10-111011593-AT-A is Benign according to our data. Variant chr10-111011593-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 928786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-111011593-AT-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00604 (912/150874) while in subpopulation NFE AF= 0.00706 (477/67544). AF 95% confidence interval is 0.00654. There are 9 homozygotes in gnomad4. There are 512 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 912 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHOC2	NM_007373.4 linkuse as main transcript	c.1541-7delT		splice_region_variant, intron_variant		ENST00000369452.9	NP_031399.2	Q9UQ13-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHOC2	ENST00000369452.9 linkuse as main transcript	c.1541-7delT		splice_region_variant, intron_variant		1	NM_007373.4	ENSP00000358464.5		Q9UQ13-1

Frequencies

GnomAD3 genomes

AF:

0.00604

AC:

911

AN:

150756

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00503

Gnomad ASJ

AF:

0.000869

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0290

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00705

Gnomad OTH

AF:

0.00530

GnomAD3 exomes

AF:

0.00704

AC:

1575

AN:

223736

Hom.:

AF XY:

0.00700

AC XY:

849

AN XY:

121300

show subpopulations

Gnomad AFR exome

AF:

0.00145

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.000662

Gnomad EAS exome

AF:

0.000356

Gnomad SAS exome

AF:

0.000221

Gnomad FIN exome

AF:

0.0337

Gnomad NFE exome

AF:

0.00836

Gnomad OTH exome

AF:

0.00714

GnomAD4 exome

AF:

0.00741

AC:

10251

AN:

1382662

Hom.:

Cov.:

AF XY:

0.00705

AC XY:

4872

AN XY:

690804

show subpopulations

Gnomad4 AFR exome

AF:

0.00155

Gnomad4 AMR exome

AF:

0.00194

Gnomad4 ASJ exome

AF:

0.000556

Gnomad4 EAS exome

AF:

0.0000517

Gnomad4 SAS exome

AF:

0.000190

Gnomad4 FIN exome

AF:

0.0278

Gnomad4 NFE exome

AF:

0.00794

Gnomad4 OTH exome

AF:

0.00652

GnomAD4 genome

AF:

0.00604

AC:

912

AN:

150874

Hom.:

Cov.:

AF XY:

0.00695

AC XY:

512

AN XY:

73694

show subpopulations

Gnomad4 AFR

AF:

0.00107

Gnomad4 AMR

AF:

0.00503

Gnomad4 ASJ

AF:

0.000869

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0290

Gnomad4 NFE

AF:

0.00706

Gnomad4 OTH

AF:

0.00525

Alfa

AF:

0.00354

Hom.:

Bravo

AF:

0.00446

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 01, 2019	Variant summary: SHOC2 c.1541-7delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.007 in 223736 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 282 fold of the estimated maximal expected allele frequency for a pathogenic variant in SHOC2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1541-7delT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	SHOC2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2019	- -

Noonan syndrome-like disorder with loose anagen hair 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 09, 2023

- -

SHOC2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

RASopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Noonan syndrome and Noonan-related syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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