14-50188589-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A208S) has been classified as Likely 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

Publications

25 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: Orphanet, ClinGen
Noonan syndrome 9
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome-like disorder with loose anagen hair
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SOS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId is 384818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 2622 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	NM_006939.4	MANE Select	c.622G>A	p.Ala208Thr	missense	Exon 5 of 23	NP_008870.2	Q07890-1
	SOS2	NM_001411020.1		c.622G>A	p.Ala208Thr	missense	Exon 5 of 22	NP_001397949.1	Q07890-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SOS2	ENST00000216373.10	TSL:1 MANE Select	c.622G>A	p.Ala208Thr	missense	Exon 5 of 23	ENSP00000216373.5	Q07890-1
SOS2	ENST00000543680.5	TSL:1	c.622G>A	p.Ala208Thr	missense	Exon 5 of 22	ENSP00000445328.1	Q07890-2
SOS2	ENST00000934708.1		c.763G>A	p.Ala255Thr	missense	Exon 6 of 24	ENSP00000604767.1

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

GnomAD2 exomes

AF:

0.0175

AC:

4304

AN:

245786

AF XY:

0.0178

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 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

African (AFR)

AF:

0.00363

AC:

120

AN:

33038

American (AMR)

AF:

0.00822

AC:

351

AN:

42692

Ashkenazi Jewish (ASJ)

AF:

0.00842

AC:

219

AN:

25998

East Asian (EAS)

AF:

0.00124

AC:

AN:

39634

South Asian (SAS)

AF:

0.00997

AC:

850

AN:

85218

European-Finnish (FIN)

AF:

0.0187

AC:

998

AN:

53266

Middle Eastern (MID)

AF:

0.00749

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0289

AC:

32047

AN:

1108674

Other (OTH)

AF:

0.0245

AC:

1473

AN:

60164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

1563

3126

4689

6252

7815

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1200

2400

3600

4800

6000

<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:

0.0172

AC:

2622

AN:

152174

Hom.:

Cov.:

AF XY:

0.0166

AC XY:

1235

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.00501

AC:

208

AN:

41536

American (AMR)

AF:

0.0119

AC:

182

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3468

East Asian (EAS)

AF:

0.00213

AC:

AN:

5174

South Asian (SAS)

AF:

0.00852

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0181

AC:

192

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0282

AC:

1917

AN:

68012

Other (OTH)

AF:

0.0161

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

124

248

373

497

621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0179

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Noonan syndrome 9 (3)

Cardiovascular phenotype (1)

Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0058

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.1

PhyloP100

6.1

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.2

REVEL

Benign

0.16

Sift

Benign

0.55

Sift4G

Benign

0.58

Polyphen

0.94

Vest4

0.34

MPC

0.69

ClinPred

0.023

GERP RS

5.6

Varity_R

0.12

gMVP

0.30

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

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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

Computational scores

Splicing

Publications

Other links and lift over