chr14-50118856-C-CA

Position:

• chr14-50118856-C-CA

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_3490-3insT 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 0.528 in 1,172,574 control chromosomes in the GnomAD database, including 122,644 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (24303 hom., cov: 0)
  • Exomes 𝑓: 0.52 (98341 hom.)
• Consequence: SOS2 NM_006939.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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-CA is Benign according to our data. Variant chr14-50118856-C-CA is described in ClinVar as [Benign]. Clinvar id is 517059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.588 AC: 83744 AN: 142358 Hom.: 24305 Cov.: 0

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.599

GnomAD3 exomes AF: 0.543 AC: 56372 AN: 103896 Hom.: 11623 AF XY: 0.543 AC XY: 30863 AN XY: 56850

Gnomad AFR exome AF: 0.474

Gnomad AMR exome AF: 0.563

Gnomad ASJ exome AF: 0.595

Gnomad EAS exome AF: 0.456

Gnomad SAS exome AF: 0.508

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.572

Gnomad OTH exome AF: 0.558

GnomAD4 exome AF: 0.520 AC: 535707 AN: 1030130 Hom.: 98341 Cov.: 24 AF XY: 0.520 AC XY: 259067 AN XY: 497984

Gnomad4 AFR exome AF: 0.416

Gnomad4 AMR exome AF: 0.537

Gnomad4 ASJ exome AF: 0.556

Gnomad4 EAS exome AF: 0.416

Gnomad4 SAS exome AF: 0.457

Gnomad4 FIN exome AF: 0.475

Gnomad4 NFE exome AF: 0.530

Gnomad4 OTH exome AF: 0.515

GnomAD4 genome AF: 0.588 AC: 83767 AN: 142444 Hom.: 24303 Cov.: 0 AF XY: 0.583 AC XY: 40143 AN XY: 68842

Gnomad4 AFR AF: 0.490

Gnomad4 AMR AF: 0.642

Gnomad4 ASJ AF: 0.706

Gnomad4 EAS AF: 0.480

Gnomad4 SAS AF: 0.550

Gnomad4 FIN AF: 0.559

Gnomad4 NFE AF: 0.640

Gnomad4 OTH AF: 0.600

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2019	Variant summary: SOS2 c.3490-4dupT alters a conserved 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 0.55 in 131430 control chromosomes, suggesting that it is the major allele and therefore benign. A ClinVar submission (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Noonan syndrome 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

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: rs10658395; hg19: chr14-50585574;