14-50138716-C-T

Variant names:

• chr14-50138716-C-T
• rs200387871
• NM_006939.4:c.2854G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006939.4(SOS2):​c.2854G>A​(p.Asp952Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,349,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D952G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.48
• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033882886).
• BP6: Variant 14-50138716-C-T is Benign according to our data. Variant chr14-50138716-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 542404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 50 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.2854G>A	p.Asp952Asn	missense	Exon 18 of 23	NP_008870.2	Q07890-1
	SOS2	NM_001411020.1		c.2755G>A	p.Asp919Asn	missense	Exon 17 of 22	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.2854G>A	p.Asp952Asn	missense	Exon 18 of 23	ENSP00000216373.5	Q07890-1
	SOS2	ENST00000543680.5	TSL:1	c.2755G>A	p.Asp919Asn	missense	Exon 17 of 22	ENSP00000445328.1	Q07890-2
	SOS2	ENST00000934708.1		c.2995G>A	p.Asp999Asn	missense	Exon 19 of 24	ENSP00000604767.1

Frequencies

GnomAD3 genomes AF: 0.000330 AC: 50 AN: 151468 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000317 AC: 72 AN: 227036 AF XY: 0.000275

Gnomad AFR exome AF: 0.0000704

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00125

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000181

Gnomad OTH exome AF: 0.000935

GnomAD4 exome AF: 0.000272 AC: 326 AN: 1198164 Hom.: 0 Cov.: 17 AF XY: 0.000267 AC XY: 162 AN XY: 607174

African (AFR) AF: 0.0000367 AC: 1 AN: 27278

American (AMR) AF: 0.00124 AC: 50 AN: 40216

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 32 AN: 23834

East Asian (EAS) AF: 0.00 AC: 0 AN: 36380

South Asian (SAS) AF: 0.00 AC: 0 AN: 74326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52036

Middle Eastern (MID) AF: 0.00155 AC: 8 AN: 5162

European-Non Finnish (NFE) AF: 0.000230 AC: 204 AN: 887980

Other (OTH) AF: 0.000608 AC: 31 AN: 50952

GnomAD4 genome AF: 0.000330 AC: 50 AN: 151584 Hom.: 0 Cov.: 32 AF XY: 0.000311 AC XY: 23 AN XY: 74034

African (AFR) AF: 0.000145 AC: 6 AN: 41308

American (AMR) AF: 0.00158 AC: 24 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10354

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67950

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000421 Hom.: 0

Bravo AF: 0.000419

ExAC AF: 0.000288 AC: 35

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Noonan syndrome 9 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	SOS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.039
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		7.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.081
Sift	Benign	0.12	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.33
MVP		0.30
MPC		0.19
ClinPred		0.047	T
GERP RS		5.6
Varity_R		0.15
gMVP		0.31
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200387871; hg19: chr14-50605434;