chr14-50138613-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The c.2957G>A (NM_006939.4(SOS2):c.2957G>A (p.Arg986Lys)) variant in SOS2 is a missense variant predicted to cause substitution of arginine by lysine at amino acid 986. The highest MAF in gnomAD v2.1.1 is 0.004629 % in the African/African American population (no population codes met). The computational predictor REVEL gives a score of 0.051, which is below the threshold of 0.3, evidence that does not predict a damaging effect on SOS2 function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy, based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP4 (Version 2.3; 12/3/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7176917/MONDO:0021060/042

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

SOS2
NM_006939.4 missense, splice_region

Scores

Splicing: ADA: 0.3495

Clinical Significance

Uncertain significance reviewed by expert panel U:3B:2

Conservation

PhyloP100: 3.81

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4 link	c.2957G>A	p.Arg986Lys	missense_variant, splice_region_variant	Exon 18 of 23	ENST00000216373.10	NP_008870.2	Q07890-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10 link	c.2957G>A	p.Arg986Lys	missense_variant, splice_region_variant	Exon 18 of 23	1	NM_006939.4	ENSP00000216373.5		Q07890-1
SOS2	ENST00000543680.5 link	c.2858G>A	p.Arg953Lys	missense_variant, splice_region_variant	Exon 17 of 22	1		ENSP00000445328.1		Q07890-2

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151672

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000157

AC:

AN:

190868

AF XY:

0.0000191

show subpopulations

Gnomad AFR exome

AF:

0.0000773

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000213

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000403

AC:

AN:

1340620

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

667300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28124

American (AMR)

AF:

0.00

AC:

AN:

28428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22408

East Asian (EAS)

AF:

0.00

AC:

AN:

35722

South Asian (SAS)

AF:

0.00

AC:

AN:

69724

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5300

European-Non Finnish (NFE)

AF:

0.0000517

AC:

AN:

1045374

Other (OTH)

AF:

0.00

AC:

AN:

54860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74002

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41258

American (AMR)

AF:

0.00

AC:

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67968

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000627

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Noonan syndrome 9

Uncertain:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 986 of the SOS2 protein (p.Arg986Lys). This variant is present in population databases (rs772746106, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with SOS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 475749). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

RASopathy

Uncertain:1

Dec 03, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The c.2957G>A (NM_006939.4(SOS2):c.2957G>A (p.Arg986Lys)) variant in SOS2 is a missense variant predicted to cause substitution of arginine by lysine at amino acid 986. The highest MAF in gnomAD v2.1.1 is 0.004629 % in the African/African American population (no population codes met). The computational predictor REVEL gives a score of 0.051, which is below the threshold of 0.3, evidence that does not predict a damaging effect on SOS2 function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy, based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP4 (Version 2.3; 12/3/2024). -

not provided

Benign:1

May 13, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

May 15, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

T;.

Eigen

Benign

-0.047

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.77

N;.

PhyloP100

3.8

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.051

Sift

Benign

0.27

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0010

B;.

Vest4

0.24

MutPred

0.40

Gain of ubiquitination at R986 (P = 0.0211);.;

MVP

0.40

MPC

0.20

ClinPred

0.28

GERP RS

5.4

Varity_R

0.58

gMVP

0.63

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.35

dbscSNV1_RF

Benign

0.30

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

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chr14-50138613-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over