14-50118856-CAA-CAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006939.4(SOS2):​c.3490-5_3490-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0512 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, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• 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: 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

Our verdict: Benign. The variant received -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 VariationId is 475752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0303 (4318/142726) while in subpopulation NFE AF = 0.0443 (2919/65964). AF 95% confidence interval is 0.0429. There are 82 homozygotes in GnomAd4. There are 2083 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4318 AD gene.

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_3490-4dupTT		splice_region intron	N/A	NP_008870.2	Q07890-1
	SOS2	NM_001411020.1		c.3391-5_3391-4dupTT		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.3490-4_3490-3insTT		splice_region intron	N/A	ENSP00000216373.5	Q07890-1
	SOS2	ENST00000543680.5	TSL:1	c.3391-4_3391-3insTT		splice_region intron	N/A	ENSP00000445328.1	Q07890-2
	SOS2	ENST00000934708.1		c.3631-4_3631-3insTT		splice_region intron	N/A	ENSP00000604767.1

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

GnomAD2 exomes AF: 0.0382 AC: 3970 AN: 103896 AF XY: 0.0403

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 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

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

African (AFR) AF: 0.0122 AC: 288 AN: 23604

American (AMR) AF: 0.0290 AC: 503 AN: 17326

Ashkenazi Jewish (ASJ) AF: 0.0364 AC: 470 AN: 12900

East Asian (EAS) AF: 0.00447 AC: 129 AN: 28860

South Asian (SAS) AF: 0.0220 AC: 710 AN: 32268

European-Finnish (FIN) AF: 0.0482 AC: 1669 AN: 34626

Middle Eastern (MID) AF: 0.0301 AC: 120 AN: 3982

European-Non Finnish (NFE) AF: 0.0602 AC: 48023 AN: 798136

Other (OTH) AF: 0.0455 AC: 1824 AN: 40062

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

African (AFR) AF: 0.00711 AC: 269 AN: 37860

American (AMR) AF: 0.0321 AC: 458 AN: 14290

Ashkenazi Jewish (ASJ) AF: 0.0209 AC: 71 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 4808

South Asian (SAS) AF: 0.00801 AC: 35 AN: 4370

European-Finnish (FIN) AF: 0.0463 AC: 413 AN: 8912

Middle Eastern (MID) AF: 0.0276 AC: 8 AN: 290

European-Non Finnish (NFE) AF: 0.0443 AC: 2919 AN: 65964

Other (OTH) AF: 0.0334 AC: 65 AN: 1946

Alfa AF: 0.0441 Hom.: 761

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Noonan syndrome 9 (3)
-	-	3	not specified (3)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	SOS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

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;