rs35530861

Variant names:

• chr14-50159939-C-T
• rs35530861
• NM_006939.4:c.1344G>A

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.1344G>A​(p.Leu448Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,614,132 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene SOS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (32 hom.)
• Consequence: SOS2 NM_006939.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.910
• 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

Specifications for SOS2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 14-50159939-C-T is Benign according to our data. Variant chr14-50159939-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 389391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.91 with no splicing effect.
• BS2: High AC in GnomAd4 at 510 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.1344G>A	p.Leu448Leu	synonymous	Exon 10 of 23	NP_008870.2	Q07890-1
	SOS2	NM_001411020.1		c.1245G>A	p.Leu415Leu	synonymous	Exon 9 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.1344G>A	p.Leu448Leu	synonymous	Exon 10 of 23	ENSP00000216373.5	Q07890-1
	SOS2	ENST00000543680.5	TSL:1	c.1245G>A	p.Leu415Leu	synonymous	Exon 9 of 22	ENSP00000445328.1	Q07890-2
	SOS2	ENST00000555794.2	TSL:1	c.456G>A	p.Leu152Leu	synonymous	Exon 4 of 6	ENSP00000484766.1	A0A087X277

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 510 AN: 152172 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00535

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00364 AC: 916 AN: 251382 AF XY: 0.00365

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00522

Gnomad NFE exome AF: 0.00611

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00462 AC: 6753 AN: 1461842 Hom.: 32 Cov.: 32 AF XY: 0.00446 AC XY: 3245 AN XY: 727222

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.000872 AC: 39 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26132

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

South Asian (SAS) AF: 0.000777 AC: 67 AN: 86254

European-Finnish (FIN) AF: 0.00515 AC: 275 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00550 AC: 6117 AN: 1111986

Other (OTH) AF: 0.00296 AC: 179 AN: 60392

GnomAD4 genome AF: 0.00335 AC: 510 AN: 152290 Hom.: 3 Cov.: 32 AF XY: 0.00295 AC XY: 220 AN XY: 74456

African (AFR) AF: 0.00118 AC: 49 AN: 41572

American (AMR) AF: 0.000981 AC: 15 AN: 15288

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00535 AC: 364 AN: 68014

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00437 Hom.: 1

Bravo AF: 0.00310

EpiCase AF: 0.00491

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Noonan syndrome 9 (3)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.2
DANN	Benign	0.66
PhyloP100		0.91
Mutation Taster		=100/0	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: rs35530861; hg19: chr14-50626657;