14-50118856-CAA-CAAA

Variant names:

• chr14-50118856-C-CA
• rs10658395
• NM_006939.4:c.3490-4dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006939.4(SOS2):​c.3490-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 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, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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-CA is Benign according to our data. Variant chr14-50118856-C-CA is described in ClinVar as Benign. ClinVar VariationId 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.

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

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

GnomAD2 exomes AF: 0.543 AC: 56372 AN: 103896 AF XY: 0.543

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 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

African (AFR) AF: 0.416 AC: 9929 AN: 23874

American (AMR) AF: 0.537 AC: 9740 AN: 18136

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 7809 AN: 14034

East Asian (EAS) AF: 0.416 AC: 12368 AN: 29722

South Asian (SAS) AF: 0.457 AC: 15022 AN: 32874

European-Finnish (FIN) AF: 0.475 AC: 16942 AN: 35634

Middle Eastern (MID) AF: 0.523 AC: 2150 AN: 4114

European-Non Finnish (NFE) AF: 0.530 AC: 440078 AN: 829706

Other (OTH) AF: 0.515 AC: 21669 AN: 42036

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

African (AFR) AF: 0.490 AC: 18476 AN: 37722

American (AMR) AF: 0.642 AC: 9158 AN: 14262

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2399 AN: 3396

East Asian (EAS) AF: 0.480 AC: 2303 AN: 4798

South Asian (SAS) AF: 0.550 AC: 2391 AN: 4350

European-Finnish (FIN) AF: 0.559 AC: 4969 AN: 8892

Middle Eastern (MID) AF: 0.662 AC: 192 AN: 290

European-Non Finnish (NFE) AF: 0.640 AC: 42170 AN: 65898

Other (OTH) AF: 0.600 AC: 1168 AN: 1946

Alfa AF: 0.417 Hom.: 761

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Noonan syndrome 9 (2)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

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

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

Other links and lift over

dbSNP: rs10658395; hg19: chr14-50585574;