14-50188639-G-C

Variant names:

• chr14-50188639-G-C
• rs72681869
• NM_006939.4:c.572C>G

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.572C>G​(p.Pro191Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00744 in 1,609,034 control chromosomes in the GnomAD database, including 58 homozygotes. 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. P191H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0078 (55 hom.)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 7.75
• Publications: 29 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011541516).
• BP6: Variant 14-50188639-G-C is Benign according to our data. Variant chr14-50188639-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 637 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	NM_006939.4	MANE Select	c.572C>G	p.Pro191Arg	missense	Exon 5 of 23	NP_008870.2
	SOS2	NM_001411020.1		c.572C>G	p.Pro191Arg	missense	Exon 5 of 22	NP_001397949.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	ENST00000216373.10	TSL:1 MANE Select	c.572C>G	p.Pro191Arg	missense	Exon 5 of 23	ENSP00000216373.5
	SOS2	ENST00000543680.5	TSL:1	c.572C>G	p.Pro191Arg	missense	Exon 5 of 22	ENSP00000445328.1
	SOS2	ENST00000556469.5	TSL:3	n.482-6033C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00419 AC: 637 AN: 152128 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00739

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00406 AC: 1011 AN: 248898 AF XY: 0.00413

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.000699

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00746

Gnomad OTH exome AF: 0.00477

GnomAD4 exome AF: 0.00778 AC: 11340 AN: 1456788 Hom.: 55 Cov.: 29 AF XY: 0.00748 AC XY: 5422 AN XY: 724972

African (AFR) AF: 0.000781 AC: 26 AN: 33280

American (AMR) AF: 0.00241 AC: 106 AN: 43946

Ashkenazi Jewish (ASJ) AF: 0.000882 AC: 23 AN: 26080

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39638

South Asian (SAS) AF: 0.000385 AC: 33 AN: 85738

European-Finnish (FIN) AF: 0.00158 AC: 84 AN: 53314

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5752

European-Non Finnish (NFE) AF: 0.00953 AC: 10567 AN: 1108822

Other (OTH) AF: 0.00824 AC: 496 AN: 60218

GnomAD4 genome AF: 0.00418 AC: 637 AN: 152246 Hom.: 3 Cov.: 31 AF XY: 0.00378 AC XY: 281 AN XY: 74430

African (AFR) AF: 0.00140 AC: 58 AN: 41536

American (AMR) AF: 0.00327 AC: 50 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000661 AC: 7 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00739 AC: 503 AN: 68032

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00585 Hom.: 4

Bravo AF: 0.00451

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.00456 AC: 554

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00743

EpiControl AF: 0.00783

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	Noonan syndrome 9 (4)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.52
Sift	Benign	0.068	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.36	B
Vest4		0.69
MVP		0.83
MPC		1.1
ClinPred		0.037	T
GERP RS		5.5
Varity_R		0.29
gMVP		0.46
Mutation Taster		=80/20	polymorphism

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: rs72681869; hg19: chr14-50655357; COSMIC: COSV99075862;