rs35530861

Positions:

• chr14-50159939-C-T

Variant summary

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

The NM_006939.4(SOS2):​c.1344G>A​(p.Leu448=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,614,132 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (32 hom.)
• Consequence: SOS2 NM_006939.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.910

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=-0.49).
• BP6: Variant 14-50159939-C-T is Benign according to our data. Variant chr14-50159939-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 389391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50159939-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.91 with no splicing effect.
• BS2: High AC in GnomAd4 at 510 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS2	NM_006939.4	c.1344G>A	p.Leu448=	synonymous_variant	10/23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.1344G>A	p.Leu448=	synonymous_variant	10/23	1	NM_006939.4	ENSP00000216373	P1
SOS2	ENST00000543680.5	c.1245G>A	p.Leu415=	synonymous_variant	9/22	1		ENSP00000445328
SOS2	ENST00000555794.2	c.459G>A	p.Leu153=	synonymous_variant	4/6	1		ENSP00000484766

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 510 AN: 152172 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00535

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00364 AC: 916 AN: 251382 Hom.: 7 AF XY: 0.00365 AC XY: 496 AN XY: 135858

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00522

Gnomad NFE exome AF: 0.00611

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00462 AC: 6753 AN: 1461842 Hom.: 32 Cov.: 32 AF XY: 0.00446 AC XY: 3245 AN XY: 727222

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.00515

Gnomad4 NFE exome AF: 0.00550

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00335 AC: 510 AN: 152290 Hom.: 3 Cov.: 32 AF XY: 0.00295 AC XY: 220 AN XY: 74456

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.00535

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00437 Hom.: 1

Bravo AF: 0.00310

EpiCase AF: 0.00491

EpiControl AF: 0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SOS2: BP4, BP7, 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.1344G>A (p.Leu448Leu) 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. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been found in a large, broad control population, ExAC in 507/121406 control chromosomes (3 homozygotes) at a frequency of 0.0041761, which is approximately 1670 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 but is cited as "Benign" by reputable database. Taken together, this variant is classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Noonan syndrome 9 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.2
DANN	Benign	0.66

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

Other links and lift over

dbSNP: rs35530861; hg19: chr14-50626657;