14-50118856-CAA-CAAAAA

Variant names:

• chr14-50118856-C-CAAA
• rs10658395
• NM_006939.4:c.3490-6_3490-4dupTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_006939.4(SOS2):​c.3490-6_3490-4dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000272 in 1,178,570 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: SOS2 NM_006939.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 14-50118856-C-CAAA is Benign according to our data. Variant chr14-50118856-C-CAAA is described in ClinVar as Benign. ClinVar VariationId is 1168547.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4	c.3490-6_3490-4dupTTT		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_3490-3insTTT		splice_region_variant, intron_variant	Intron 22 of 22	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.3391-4_3391-3insTTT		splice_region_variant, intron_variant	Intron 21 of 21	1		ENSP00000445328.1

Frequencies

GnomAD3 genomes AF: 0.0000210 AC: 3 AN: 142700 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000303

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000154 AC: 16 AN: 103896 AF XY: 0.000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000210

Gnomad ASJ exome AF: 0.000541

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000849

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000307 AC: 318 AN: 1035870 Hom.: 0 Cov.: 24 AF XY: 0.000320 AC XY: 160 AN XY: 500716

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

African (AFR) AF: 0.00 AC: 0 AN: 24170

American (AMR) AF: 0.000110 AC: 2 AN: 18240

Ashkenazi Jewish (ASJ) AF: 0.000213 AC: 3 AN: 14094

East Asian (EAS) AF: 0.00 AC: 0 AN: 29924

South Asian (SAS) AF: 0.000121 AC: 4 AN: 33188

European-Finnish (FIN) AF: 0.000195 AC: 7 AN: 35874

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4132

European-Non Finnish (NFE) AF: 0.000345 AC: 288 AN: 834000

Other (OTH) AF: 0.000308 AC: 13 AN: 42248

⚠️ 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: 0.0000210 AC: 3 AN: 142700 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 68936

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

African (AFR) AF: 0.00 AC: 0 AN: 37762

American (AMR) AF: 0.00 AC: 0 AN: 14282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 4820

South Asian (SAS) AF: 0.00 AC: 0 AN: 4376

European-Finnish (FIN) AF: 0.000112 AC: 1 AN: 8928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000303 AC: 2 AN: 66008

Other (OTH) AF: 0.00 AC: 0 AN: 1928

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0662318), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 761

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Noonan syndrome 9 Benign:1

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SOS2-related disorder Benign:1

Aug 17, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

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

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;