chr14-50182600-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4BP6BS2

The NM_006939.4(SOS2):c.721G>A(p.Glu241Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,596,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SOS2
NM_006939.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.91

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 Likely_benign. Variant got -4 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=0.28850034).

BP6

Variant 14-50182600-C-T is Benign according to our data. Variant chr14-50182600-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 570816.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4 link	c.721G>A	p.Glu241Lys	missense_variant	Exon 6 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.721G>A	p.Glu241Lys	missense_variant	Exon 6 of 23	1	NM_006939.4	ENSP00000216373.5	Q07890-1
SOS2	ENST00000543680.5 link	c.721G>A	p.Glu241Lys	missense_variant	Exon 6 of 22	1		ENSP00000445328.1	Q07890-2
SOS2	ENST00000556469.5 link	n.488G>A		non_coding_transcript_exon_variant	Exon 5 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

151954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

243570

Hom.:

AF XY:

0.00000759

AC XY:

AN XY:

131716

show subpopulations

Gnomad AFR exome

AF:

0.000189

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000554

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000554

AC:

AN:

1444538

Hom.:

Cov.:

AF XY:

0.00000417

AC XY:

AN XY:

719188

show subpopulations

Gnomad4 AFR exome

AF:

0.0000609

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000363

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000724

AC:

AN:

151954

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74210

show subpopulations

Gnomad4 AFR

AF:

0.000218

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000674

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Noonan syndrome 9

Uncertain:1Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Oct 19, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;.

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.047

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.97

D;.

Vest4

0.32

MVP

0.58

MPC

1.2

ClinPred

0.94

GERP RS

5.5

Varity_R

0.57

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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