rs111961549

Variant names:

• chr14-50161607-T-C
• rs111961549
• NM_006939.4:c.1071A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-50161607-T-C
• chr14-50161607-T-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PP3_Moderate BP6_Very_Strong BS2

The NM_006939.4(SOS2):​c.1071A>G​(p.Gln357Gln) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000846 in 1,609,548 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). The gene SOS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (2 hom.)
• Consequence: SOS2 NM_006939.4 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.03
• 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: 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 -10 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 14-50161607-T-C is Benign according to our data. Variant chr14-50161607-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 67 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.1071A>G	p.Gln357Gln	splice_region synonymous	Exon 9 of 23	NP_008870.2	Q07890-1
	SOS2	NM_001411020.1		c.972A>G	p.Gln324Gln	splice_region synonymous	Exon 8 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.1071A>G	p.Gln357Gln	splice_region synonymous	Exon 9 of 23	ENSP00000216373.5	Q07890-1
	SOS2	ENST00000543680.5	TSL:1	c.972A>G	p.Gln324Gln	splice_region synonymous	Exon 8 of 22	ENSP00000445328.1	Q07890-2
	SOS2	ENST00000555794.2	TSL:1	c.183A>G	p.Gln61Gln	splice_region synonymous	Exon 3 of 6	ENSP00000484766.1	A0A087X277

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000338 AC: 83 AN: 245800 AF XY: 0.000384

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000603

Gnomad ASJ exome AF: 0.000607

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000643

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000888 AC: 1294 AN: 1457422 Hom.: 2 Cov.: 29 AF XY: 0.000846 AC XY: 613 AN XY: 724822

African (AFR) AF: 0.000150 AC: 5 AN: 33258

American (AMR) AF: 0.0000457 AC: 2 AN: 43740

Ashkenazi Jewish (ASJ) AF: 0.000385 AC: 10 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 85086

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00106 AC: 1178 AN: 1110526

Other (OTH) AF: 0.00156 AC: 94 AN: 60258

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74306

African (AFR) AF: 0.0000965 AC: 4 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68020

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000638 Hom.: 0

Bravo AF: 0.000431

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Benign	0.91
PhyloP100		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs111961549; hg19: chr14-50628325;