NM_006939.4:c.3490-5_3490-4delTT

Variant names:

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

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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: 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: 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

Selected	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
	SOS2	NM_001411020.1		c.3391-5_3391-4delTT		splice_region intron	N/A	NP_001397949.1

Ensembl Transcripts

Selected	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
	SOS2	ENST00000543680.5	TSL:1	c.3391-5_3391-4delTT		splice_region intron	N/A	ENSP00000445328.1

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;