chr14-50118856-C-CAA

Position:

• chr14-50118856-C-CAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006939.4(SOS2):​c.3490-4_3490-3insTT variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.39

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 -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 id is 475752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS2	NM_006939.4	c.3490-4_3490-3insTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.3490-4_3490-3insTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006939.4	ENSP00000216373	P1
SOS2	ENST00000543680.5	c.3391-4_3391-3insTT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000445328

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

GnomAD3 exomes AF: 0.0382 AC: 3970 AN: 103896 Hom.: 41 AF XY: 0.0403 AC XY: 2289 AN XY: 56850

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 SAS exome AF: 0.0157

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

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.0290

Gnomad4 ASJ exome AF: 0.0364

Gnomad4 EAS exome AF: 0.00447

Gnomad4 SAS exome AF: 0.0220

Gnomad4 FIN exome AF: 0.0482

Gnomad4 NFE exome AF: 0.0602

Gnomad4 OTH exome AF: 0.0455

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

Gnomad4 AFR AF: 0.00711

Gnomad4 AMR AF: 0.0321

Gnomad4 ASJ AF: 0.0209

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00801

Gnomad4 FIN AF: 0.0463

Gnomad4 NFE AF: 0.0443

Gnomad4 OTH AF: 0.0334

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 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. -

SOS2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 06, 2020

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10658395; hg19: chr14-50585574;