14-50188589-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_006939.4(SOS2):c.622G>A(p.Ala208Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0241 in 1,606,596 control chromosomes in the GnomAD database, including 545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 20 hom., cov: 31)

Exomes 𝑓: 0.025 ( 525 hom. )

Consequence

SOS2
NM_006939.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 6.15

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 made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain DH (size 190) in uniprot entity SOS2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006939.4

BP4

Computational evidence support a benign effect (MetaRNN=0.005761385).

BP6

Variant 14-50188589-C-T is Benign according to our data. Variant chr14-50188589-C-T is described in ClinVar as [Benign]. Clinvar id is 384818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50188589-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0172 (2622/152174) while in subpopulation NFE AF= 0.0282 (1917/68012). AF 95% confidence interval is 0.0271. There are 20 homozygotes in gnomad4. There are 1235 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2622 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4 link	c.622G>A	p.Ala208Thr	missense_variant	Exon 5 of 23	ENST00000216373.10	NP_008870.2	Q07890-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SOS2	ENST00000216373.10 link	c.622G>A	p.Ala208Thr	missense_variant	Exon 5 of 23	1	NM_006939.4	ENSP00000216373.5	Q07890-1
SOS2	ENST00000543680.5 link	c.622G>A	p.Ala208Thr	missense_variant	Exon 5 of 22	1		ENSP00000445328.1	Q07890-2
SOS2	ENST00000556469.5 link	n.482-5983G>A		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2622

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00502

Gnomad AMI

AF:

0.00879

Gnomad AMR

AF:

0.0119

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.00851

Gnomad FIN

AF:

0.0181

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0282

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.0175

AC:

4304

AN:

245786

Hom.:

AF XY:

0.0178

AC XY:

2367

AN XY:

133054

show subpopulations

Gnomad AFR exome

AF:

0.00409

Gnomad AMR exome

AF:

0.00761

Gnomad ASJ exome

AF:

0.00799

Gnomad EAS exome

AF:

0.00195

Gnomad SAS exome

AF:

0.00967

Gnomad FIN exome

AF:

0.0200

Gnomad NFE exome

AF:

0.0272

Gnomad OTH exome

AF:

0.0183

GnomAD4 exome

AF:

0.0249

AC:

36150

AN:

1454422

Hom.:

525

Cov.:

AF XY:

0.0244

AC XY:

17644

AN XY:

723780

show subpopulations

Gnomad4 AFR exome

AF:

0.00363

Gnomad4 AMR exome

AF:

0.00822

Gnomad4 ASJ exome

AF:

0.00842

Gnomad4 EAS exome

AF:

0.00124

Gnomad4 SAS exome

AF:

0.00997

Gnomad4 FIN exome

AF:

0.0187

Gnomad4 NFE exome

AF:

0.0289

Gnomad4 OTH exome

AF:

0.0245

GnomAD4 genome

AF:

0.0172

AC:

2622

AN:

152174

Hom.:

Cov.:

AF XY:

0.0166

AC XY:

1235

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00501

Gnomad4 AMR

AF:

0.0119

Gnomad4 ASJ

AF:

0.00836

Gnomad4 EAS

AF:

0.00213

Gnomad4 SAS

AF:

0.00852

Gnomad4 FIN

AF:

0.0181

Gnomad4 NFE

AF:

0.0282

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0199

Hom.:

Bravo

AF:

0.0161

TwinsUK

AF:

0.0305

AC:

113

ALSPAC

AF:

0.0278

AC:

107

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0277

AC:

238

ExAC

AF:

0.0185

AC:

2245

EpiCase

AF:

0.0269

EpiControl

AF:

0.0251

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SOS2: BS1, BS2 -

Apr 12, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SOS2 c.622G>A (p.Ala208Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2245/121196 control chromosomes at a frequency of 0.0185237, which is approximately 7409 times the estimated maximal expected allele frequency of a pathogenic SOS2 variant (0.0000025), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Oct 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Noonan syndrome 9

Benign:3

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 12, 2019

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

Jul 08, 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

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;T

MetaRNN

Benign

0.0058

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.16

Sift

Benign

0.55

T;T

Sift4G

Benign

0.58

T;T

Polyphen

0.94

P;.

Vest4

0.34

MPC

0.69

ClinPred

0.023

GERP RS

5.6

Varity_R

0.12

gMVP

0.30

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