14-50118856-CAA-CA

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_006939.4(SOS2):c.3490-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,174,898 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0013 ( 13 hom. )

Consequence

SOS2
NM_006939.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.39

Publications

4 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 -12 ACMG points.

BP6

Variant 14-50118856-CA-C is Benign according to our data. Variant chr14-50118856-CA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 706888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 72 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006939.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	NM_006939.4	MANE Select	c.3490-4delT		splice_region intron	N/A	NP_008870.2
	SOS2	NM_001411020.1		c.3391-4delT		splice_region intron	N/A	NP_001397949.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	ENST00000216373.10	TSL:1 MANE Select	c.3490-4delT		splice_region intron	N/A	ENSP00000216373.5
	SOS2	ENST00000543680.5	TSL:1	c.3391-4delT		splice_region intron	N/A	ENSP00000445328.1

Frequencies

GnomAD3 genomes

AF:

0.000512

AC:

AN:

142682

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000212

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000700

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000415

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.000112

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000152

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00342

AC:

355

AN:

103896

AF XY:

0.00399

show subpopulations

Gnomad AFR exome

AF:

0.00395

Gnomad AMR exome

AF:

0.00210

Gnomad ASJ exome

AF:

0.00379

Gnomad EAS exome

AF:

0.00305

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.00429

GnomAD4 exome

AF:

0.00129

AC:

1336

AN:

1032128

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

745

AN XY:

499010

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00134

AC:

AN:

23962

American (AMR)

AF:

0.000991

AC:

AN:

18162

Ashkenazi Jewish (ASJ)

AF:

0.000426

AC:

AN:

14072

East Asian (EAS)

AF:

0.000909

AC:

AN:

29700

South Asian (SAS)

AF:

0.0190

AC:

625

AN:

32922

European-Finnish (FIN)

AF:

0.00126

AC:

AN:

35734

Middle Eastern (MID)

AF:

0.00170

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.000618

AC:

514

AN:

831394

Other (OTH)

AF:

0.00147

AC:

AN:

42056

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.355

Heterozygous variant carriers

117

234

351

468

585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.000504

AC:

AN:

142770

Hom.:

Cov.:

AF XY:

0.000637

AC XY:

AN XY:

69026

show subpopulations

African (AFR)

AF:

0.000211

AC:

AN:

37862

American (AMR)

AF:

0.0000700

AC:

AN:

14294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3396

East Asian (EAS)

AF:

0.000416

AC:

AN:

4808

South Asian (SAS)

AF:

0.0135

AC:

AN:

4368

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

8924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000152

AC:

AN:

65990

Other (OTH)

AF:

0.00

AC:

AN:

1948

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:

0.00

Hom.:

761

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 9

Benign:3

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 19, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Oct 21, 2019

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.3490-4delT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 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 0.0034 in 103896 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 1367 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3490-4delT 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.

SOS2-related disorder

Benign:1

Apr 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

not provided

Benign:1

Sep 20, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Nov 21, 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 09, 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 v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.4

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.24

Position offset: -3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over