14-50188589-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000216373.10(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
ENST00000216373.10 missense

Scores

1
5
12

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 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/exons MANE Protein UniProt
SOS2NM_006939.4 linkuse as main transcriptc.622G>A p.Ala208Thr missense_variant 5/23 ENST00000216373.10 NP_008870.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SOS2ENST00000216373.10 linkuse as main transcriptc.622G>A p.Ala208Thr missense_variant 5/231 NM_006939.4 ENSP00000216373 P1Q07890-1
SOS2ENST00000543680.5 linkuse as main transcriptc.622G>A p.Ala208Thr missense_variant 5/221 ENSP00000445328 Q07890-2
SOS2ENST00000556469.5 linkuse as main transcriptn.482-5983G>A intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0172
AC:
2622
AN:
152056
Hom.:
20
Cov.:
31
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.:
51
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.:
29
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.:
20
Cov.:
31
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.:
27
Bravo
AF:
0.0161
TwinsUK
AF:
0.0305
AC:
113
ALSPAC
AF:
0.0278
AC:
107
ESP6500AA
AF:
0.00704
AC:
31
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
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024SOS2: BS1, BS2 -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxOct 25, 2016This 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. -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 12, 2017Variant 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. -
Noonan syndrome 9 Benign:3
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 09, 2023- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou Lab-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 12, 2019This 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
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJul 08, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.098
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.11
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.27
T;.
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.83
T;T
MetaRNN
Benign
0.0058
T;T
MetaSVM
Benign
-0.76
T
MutationAssessor
Uncertain
2.1
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.68
T
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
T
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.

Other links and lift over

dbSNP: rs61755579; hg19: chr14-50655307; COSMIC: COSV105864124; API