rs34139502

Positions:

• chr14-50157042-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006939.4(SOS2):​c.2014C>A​(p.Leu672Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000958 in 1,611,986 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (4 hom.)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.89

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005838603).
• BP6: Variant 14-50157042-G-T is Benign according to our data. Variant chr14-50157042-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 445827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0052 (791/152044) while in subpopulation AFR AF= 0.0176 (732/41482). AF 95% confidence interval is 0.0166. There are 8 homozygotes in gnomad4. There are 390 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 791 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS2	NM_006939.4	c.2014C>A	p.Leu672Ile	missense_variant	12/23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.2014C>A	p.Leu672Ile	missense_variant	12/23	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.1915C>A	p.Leu639Ile	missense_variant	11/22	1		ENSP00000445328.1
SOS2	ENST00000555794.2	c.1126C>A	p.Leu376Ile	missense_variant	6/6	1		ENSP00000484766.1

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 789 AN: 151926 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

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: 0.000191

Gnomad OTH AF: 0.00480

GnomAD3 exomes AF: 0.00133 AC: 334 AN: 250222 Hom.: 4 AF XY: 0.000887 AC XY: 120 AN XY: 135218

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000516 AC: 753 AN: 1459942 Hom.: 4 Cov.: 30 AF XY: 0.000420 AC XY: 305 AN XY: 726244

Gnomad4 AFR exome AF: 0.0170

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00520 AC: 791 AN: 152044 Hom.: 8 Cov.: 32 AF XY: 0.00525 AC XY: 390 AN XY: 74332

Gnomad4 AFR AF: 0.0176

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00475

Alfa AF: 0.000541 Hom.: 1

Bravo AF: 0.00583

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00171 AC: 208

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 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 provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 20, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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.2014C>A (p.Leu672Ile) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the Ras guanine nucleotide exchange factor domain and Ras-like guanine nucleotide exchange factor domain, N-terminal (InterPro). 4/5 in silico tools predict a benign outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0019927 (208/104380 control chromosomes [3 homozygotes] in all populations), but was primarily observed in the African subpopulation at a frequency of 0.020296 (189/9312 controls chromosomes [3 homozygotes]). This frequency is about 8118 times the estimated maximal expected allele frequency of a pathogenic SOS2 variant (0.0000025), which provides strong evidence that this is likely a benign polymorphism found primarily in populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2017

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. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2022

This alteration is classified as likely 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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	0.082
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.072
Sift	Benign	0.20	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.010	B;.
Vest4		0.47
MVP		0.30
MPC		1.4
ClinPred		0.018	T
GERP RS		5.0
Varity_R		0.53
gMVP		0.46

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: rs34139502; hg19: chr14-50623760;