14-50118856-CAA-CAAAA

Variant names:

• chr14-50118856-C-CAA
• rs10658395
• NM_006939.4:c.3490-5_3490-4dupTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006939.4(SOS2):​c.3490-5_3490-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0512 in 1,134,490 control chromosomes in the GnomAD database, including 378 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (82 hom., cov: 0)
  • Exomes 𝑓: 0.054 (296 hom.)
• Consequence: SOS2 NM_006939.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.39
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 9

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 14-50118856-C-CAA is Benign according to our data. Variant chr14-50118856-C-CAA is described in ClinVar as Benign. ClinVar VariationId is 475752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0303 (4318/142726) while in subpopulation NFE AF = 0.0443 (2919/65964). AF 95% confidence interval is 0.0429. There are 82 homozygotes in GnomAd4. There are 2083 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4318 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4	c.3490-5_3490-4dupTT		splice_region_variant, intron_variant	Intron 22 of 22	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.3490-4_3490-3insTT		splice_region_variant, intron_variant	Intron 22 of 22	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.3391-4_3391-3insTT		splice_region_variant, intron_variant	Intron 21 of 21	1		ENSP00000445328.1

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4322 AN: 142640 Hom.: 82 Cov.: 0

Gnomad AFR AF: 0.00712

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0321

Gnomad ASJ AF: 0.0209

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00822

Gnomad FIN AF: 0.0463

Gnomad MID AF: 0.0323

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.0337

GnomAD2 exomes AF: 0.0382 AC: 3970 AN: 103896 AF XY: 0.0403

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.0330

Gnomad EAS exome AF: 0.00559

Gnomad FIN exome AF: 0.0498

Gnomad NFE exome AF: 0.0505

Gnomad OTH exome AF: 0.0377

GnomAD4 exome AF: 0.0542 AC: 53736 AN: 991764 Hom.: 296 Cov.: 24 AF XY: 0.0539 AC XY: 25812 AN XY: 478790

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0122 AC: 288 AN: 23604

American (AMR) AF: 0.0290 AC: 503 AN: 17326

Ashkenazi Jewish (ASJ) AF: 0.0364 AC: 470 AN: 12900

East Asian (EAS) AF: 0.00447 AC: 129 AN: 28860

South Asian (SAS) AF: 0.0220 AC: 710 AN: 32268

European-Finnish (FIN) AF: 0.0482 AC: 1669 AN: 34626

Middle Eastern (MID) AF: 0.0301 AC: 120 AN: 3982

European-Non Finnish (NFE) AF: 0.0602 AC: 48023 AN: 798136

Other (OTH) AF: 0.0455 AC: 1824 AN: 40062

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0303 AC: 4318 AN: 142726 Hom.: 82 Cov.: 0 AF XY: 0.0302 AC XY: 2083 AN XY: 68992

African (AFR) AF: 0.00711 AC: 269 AN: 37860

American (AMR) AF: 0.0321 AC: 458 AN: 14290

Ashkenazi Jewish (ASJ) AF: 0.0209 AC: 71 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 4808

South Asian (SAS) AF: 0.00801 AC: 35 AN: 4370

European-Finnish (FIN) AF: 0.0463 AC: 413 AN: 8912

Middle Eastern (MID) AF: 0.0276 AC: 8 AN: 290

European-Non Finnish (NFE) AF: 0.0443 AC: 2919 AN: 65964

Other (OTH) AF: 0.0334 AC: 65 AN: 1946

Alfa AF: 0.0441 Hom.: 761

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Aug 19, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SOS2 c.3490-5_3490-4dupTT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.038 in 103896 control chromosomes in the gnomAD database (exomes dataset), including 41 homozygotes. The observed variant frequency is approximately 15000 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3490-5_3490-4dupTT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cited the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Nov 01, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome 9 Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SOS2-related disorder Benign:1

Apr 06, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Noonan syndrome and Noonan-related syndrome Benign:1

Jul 08, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10658395; hg19: chr14-50585574;