rs10658395

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr14-50118856-CAA-C
• chr14-50118856-CAA-CA
• chr14-50118856-CAA-CAAA
• chr14-50118856-CAA-CAAAA
• chr14-50118856-CAA-CAAAAA
• chr14-50118856-CAA-CAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006939.4(SOS2):​c.3490-5_3490-4delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000289 in 1,036,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as (no stars). The gene SOS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: SOS2 NM_006939.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.91
• Publications: 0 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: Orphanet, ClinGen
• Noonan syndrome 9

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Specifications for SOS2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006939.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	NM_006939.4	MANE Select	c.3490-5_3490-4delTT		splice_region intron	N/A	NP_008870.2	Q07890-1
	SOS2	NM_001411020.1		c.3391-5_3391-4delTT		splice_region intron	N/A	NP_001397949.1	Q07890-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	ENST00000216373.10	TSL:1 MANE Select	c.3490-5_3490-4delTT		splice_region intron	N/A	ENSP00000216373.5	Q07890-1
	SOS2	ENST00000543680.5	TSL:1	c.3391-5_3391-4delTT		splice_region intron	N/A	ENSP00000445328.1	Q07890-2
	SOS2	ENST00000934708.1		c.3631-5_3631-4delTT		splice_region intron	N/A	ENSP00000604767.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000289 AC: 3 AN: 1036876 Hom.: 0 AF XY: 0.00000399 AC XY: 2 AN XY: 501212

⚠️ 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: 24182

American (AMR) AF: 0.00 AC: 0 AN: 18254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14106

East Asian (EAS) AF: 0.00 AC: 0 AN: 29928

South Asian (SAS) AF: 0.00 AC: 0 AN: 33210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000359 AC: 3 AN: 834872

Other (OTH) AF: 0.00 AC: 0 AN: 42286

⚠️ 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 Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: 32
DS_AL_spliceai		0.36		Position offset: -3

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

Other links and lift over

dbSNP: rs10658395; hg19: chr14-50585574;