14-50188620-T-C

Variant names:

• chr14-50188620-T-C
• rs113460230
• NM_006939.4:c.591A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006939.4(SOS2):​c.591A>G​(p.Leu197Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00908 in 1,610,384 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0092 (85 hom.)
• Consequence: SOS2 NM_006939.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0610
• Publications: 2 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 14-50188620-T-C is Benign according to our data. Variant chr14-50188620-T-C is described in ClinVar as Benign. ClinVar VariationId is 386529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.061 with no splicing effect.
• BS2: High AC in GnomAd4 at 1227 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.591A>G	p.Leu197Leu	synonymous	Exon 5 of 23	NP_008870.2
	SOS2	NM_001411020.1		c.591A>G	p.Leu197Leu	synonymous	Exon 5 of 22	NP_001397949.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	ENST00000216373.10	TSL:1 MANE Select	c.591A>G	p.Leu197Leu	synonymous	Exon 5 of 23	ENSP00000216373.5
	SOS2	ENST00000543680.5	TSL:1	c.591A>G	p.Leu197Leu	synonymous	Exon 5 of 22	ENSP00000445328.1
	SOS2	ENST00000934708.1		c.732A>G	p.Leu244Leu	synonymous	Exon 6 of 24	ENSP00000604767.1

Frequencies

GnomAD3 genomes AF: 0.00807 AC: 1228 AN: 152184 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.00911

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00751 AC: 1875 AN: 249680 AF XY: 0.00774

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00550

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00954

GnomAD4 exome AF: 0.00919 AC: 13401 AN: 1458082 Hom.: 85 Cov.: 29 AF XY: 0.00925 AC XY: 6712 AN XY: 725598

African (AFR) AF: 0.00174 AC: 58 AN: 33328

American (AMR) AF: 0.00560 AC: 247 AN: 44138

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00289 AC: 248 AN: 85892

European-Finnish (FIN) AF: 0.0109 AC: 582 AN: 53354

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5758

European-Non Finnish (NFE) AF: 0.0105 AC: 11698 AN: 1109598

Other (OTH) AF: 0.00884 AC: 533 AN: 60276

GnomAD4 genome AF: 0.00806 AC: 1227 AN: 152302 Hom.: 6 Cov.: 31 AF XY: 0.00837 AC XY: 623 AN XY: 74464

African (AFR) AF: 0.00147 AC: 61 AN: 41580

American (AMR) AF: 0.00909 AC: 139 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.0127 AC: 135 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0115 AC: 782 AN: 68020

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.0101 Hom.: 16

Bravo AF: 0.00727

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.00931

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Noonan syndrome 9 (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.5
DANN	Benign	0.80
PhyloP100		-0.061
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs113460230; hg19: chr14-50655338;