14-50118794-TGGA-TGGAGGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PM4_SupportingBP6_Very_StrongBS2

The NM_006939.4(SOS2):c.3546_3548dupTCC(p.Pro1183dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000163 in 1,556,390 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1183P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

SOS2
NM_006939.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 5.66

Publications

0 publications found

Variant links:

Genes affected

SOS2 (HGNC:11188): (SOS Ras/Rho guanine nucleotide exchange factor 2) This gene encodes a regulatory protein that is involved in the positive regulation of ras proteins. Mutations in this gene are associated with Noonan Syndrome-9. [provided by RefSeq, Jul 2016]

SOS2 Gene-Disease associations (from GenCC):

Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Noonan syndrome 9
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P

SOS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_006939.4. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 14-50118794-T-TGGA is Benign according to our data. Variant chr14-50118794-T-TGGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4 link	c.3546_3548dupTCC	p.Pro1183dup	disruptive_inframe_insertion	Exon 23 of 23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10 link	c.3546_3548dupTCC	p.Pro1183dup	disruptive_inframe_insertion	Exon 23 of 23	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5 link	c.3447_3449dupTCC	p.Pro1150dup	disruptive_inframe_insertion	Exon 22 of 22	1		ENSP00000445328.1

Frequencies

GnomAD3 genomes

AF:

0.000192

AC:

AN:

146170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00670

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000747

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000329

AC:

AN:

230798

AF XY:

0.000325

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00755

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000663

Gnomad OTH exome

AF:

0.000367

GnomAD4 exome

AF:

0.000160

AC:

226

AN:

1410220

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

123

AN XY:

697792

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32226

American (AMR)

AF:

0.0000246

AC:

AN:

40592

Ashkenazi Jewish (ASJ)

AF:

0.00724

AC:

178

AN:

24602

East Asian (EAS)

AF:

0.00

AC:

AN:

38316

South Asian (SAS)

AF:

0.00

AC:

AN:

80546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5540

European-Non Finnish (NFE)

AF:

0.0000232

AC:

AN:

1078822

Other (OTH)

AF:

0.000381

AC:

AN:

57734

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000192

AC:

AN:

146170

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

AN XY:

70850

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39320

American (AMR)

AF:

0.00

AC:

AN:

14200

Ashkenazi Jewish (ASJ)

AF:

0.00670

AC:

AN:

3432

East Asian (EAS)

AF:

0.00

AC:

AN:

4988

South Asian (SAS)

AF:

0.00

AC:

AN:

4614

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0000747

AC:

AN:

66928

Other (OTH)

AF:

0.00

AC:

AN:

1960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00113

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 9

Benign:4

Sep 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 22, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:2

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SOS2: PM4:Supporting, BS1 -

Dec 15, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SOS2 c.3546_3548dupTCC (p.Pro1183dup) results in an in-frame duplication that is predicted to duplicate 1 amino acid into the encoded protein. The variant allele was found at a frequency of 0.00033 in 230798 control chromosomes (gnomAD). The observed variant frequency is approximately 132 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3546_3548dupTCC in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed this variant since 2014: two classified the variant as likely benign, and three as benign. Based on the evidence outlined above, the variant was classified as benign. -

Cardiovascular phenotype

Benign:1

Jan 18, 2022

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Noonan syndrome and Noonan-related syndrome

Benign:1

Apr 06, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.7

Mutation Taster

=66/34

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over