14-50188620-T-C

Position:

• chr14-50188620-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The ENST00000216373.10(SOS2):​c.591A>G​(p.Leu197=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00908 in 1,610,384 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0092 (85 hom.)
• Consequence: SOS2 ENST00000216373.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0610

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 14-50188620-T-C is Benign according to our data. Variant chr14-50188620-T-C is described in ClinVar as [Benign]. Clinvar id is 386529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50188620-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.061 with no splicing effect.
• BS2: High AC in GnomAd4 at 1227 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS2	NM_006939.4	c.591A>G	p.Leu197=	synonymous_variant	5/23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.591A>G	p.Leu197=	synonymous_variant	5/23	1	NM_006939.4	ENSP00000216373	P1
SOS2	ENST00000543680.5	c.591A>G	p.Leu197=	synonymous_variant	5/22	1		ENSP00000445328
SOS2	ENST00000556469.5	n.482-6014A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00807 AC: 1228 AN: 152184 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.00911

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00751 AC: 1875 AN: 249680 Hom.: 19 AF XY: 0.00774 AC XY: 1046 AN XY: 135064

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00550

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00273

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00954

GnomAD4 exome AF: 0.00919 AC: 13401 AN: 1458082 Hom.: 85 Cov.: 29 AF XY: 0.00925 AC XY: 6712 AN XY: 725598

Gnomad4 AFR exome AF: 0.00174

Gnomad4 AMR exome AF: 0.00560

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00289

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.00884

GnomAD4 genome AF: 0.00806 AC: 1227 AN: 152302 Hom.: 6 Cov.: 31 AF XY: 0.00837 AC XY: 623 AN XY: 74464

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00909

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0127

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00976 Hom.: 5

Bravo AF: 0.00727

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.00931

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SOS2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 12, 2017	Variant summary: The SOS2 c.591A>G (p.Leu197Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts that this variant does not affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC at a frequency of 0.007386 (893/120904 control chromosomes [9 homozygotes]), which is approximately 2954 times the estimated maximal expected allele frequency of a pathogenic SOS2 variant (0.0000025), providing strong evidence that this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Noonan syndrome 9 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 27, 2018

p.Leu197Leu in exon 5 of SOS2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 1.08% (718/66434) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs113460230). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2020

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.5
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs113460230; hg19: chr14-50655338;