rs35396088

Variant names:

• chr14-50182505-A-G
• rs35396088
• NM_006939.4:c.816T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006939.4(SOS2):​c.816T>C​(p.Ser272Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,613,700 control chromosomes in the GnomAD database, including 645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (75 hom., cov: 32)
  • Exomes 𝑓: 0.024 (570 hom.)
• Consequence: SOS2 NM_006939.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.199
• Publications: 6 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 14-50182505-A-G is Benign according to our data. Variant chr14-50182505-A-G is described in ClinVar as Benign. ClinVar VariationId is 475762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.199 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0205 (3120/152334) while in subpopulation NFE AF = 0.0258 (1756/68026). AF 95% confidence interval is 0.0248. There are 75 homozygotes in GnomAd4. There are 1732 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3120 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.816T>C	p.Ser272Ser	synonymous	Exon 6 of 23	NP_008870.2
	SOS2	NM_001411020.1		c.816T>C	p.Ser272Ser	synonymous	Exon 6 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.816T>C	p.Ser272Ser	synonymous	Exon 6 of 23	ENSP00000216373.5
	SOS2	ENST00000543680.5	TSL:1	c.816T>C	p.Ser272Ser	synonymous	Exon 6 of 22	ENSP00000445328.1
	SOS2	ENST00000934708.1		c.957T>C	p.Ser319Ser	synonymous	Exon 7 of 24	ENSP00000604767.1

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3120 AN: 152216 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0927

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.0220 AC: 5525 AN: 251286 AF XY: 0.0220

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.00564

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0906

Gnomad NFE exome AF: 0.0264

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0236 AC: 34544 AN: 1461366 Hom.: 570 Cov.: 30 AF XY: 0.0231 AC XY: 16822 AN XY: 726998

African (AFR) AF: 0.00341 AC: 114 AN: 33480

American (AMR) AF: 0.00588 AC: 263 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 355 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00208 AC: 179 AN: 86254

European-Finnish (FIN) AF: 0.0883 AC: 4712 AN: 53380

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0250 AC: 27769 AN: 1111564

Other (OTH) AF: 0.0188 AC: 1136 AN: 60380

GnomAD4 genome AF: 0.0205 AC: 3120 AN: 152334 Hom.: 75 Cov.: 32 AF XY: 0.0232 AC XY: 1732 AN XY: 74500

African (AFR) AF: 0.00390 AC: 162 AN: 41584

American (AMR) AF: 0.00850 AC: 130 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.0927 AC: 984 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0258 AC: 1756 AN: 68026

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.0216 Hom.: 22

Bravo AF: 0.0133

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0191

EpiControl AF: 0.0210

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.2
DANN	Benign	0.79
PhyloP100		0.20
Mutation Taster		=67/33	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: rs35396088; hg19: chr14-50649223;