NM_006939.4:c.2443A>G

Variant names:

• chr14-50145538-T-C
• rs886041958
• NM_006939.4:c.2443A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_006939.4(SOS2):​c.2443A>G​(p.Asn815Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene SOS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.21
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28242046).
• BP6: Variant 14-50145538-T-C is Benign according to our data. Variant chr14-50145538-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 280818.

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.2443A>G	p.Asn815Asp	missense	Exon 15 of 23	NP_008870.2	Q07890-1
	SOS2	NM_001411020.1		c.2344A>G	p.Asn782Asp	missense	Exon 14 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.2443A>G	p.Asn815Asp	missense	Exon 15 of 23	ENSP00000216373.5	Q07890-1
	SOS2	ENST00000543680.5	TSL:1	c.2344A>G	p.Asn782Asp	missense	Exon 14 of 22	ENSP00000445328.1	Q07890-2
	SOS2	ENST00000934708.1		c.2584A>G	p.Asn862Asp	missense	Exon 16 of 24	ENSP00000604767.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458402 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725524

African (AFR) AF: 0.00 AC: 0 AN: 33340

American (AMR) AF: 0.00 AC: 0 AN: 44266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 85500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110222

Other (OTH) AF: 0.00 AC: 0 AN: 60302

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Noonan syndrome 9 (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		6.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.072
Sift	Benign	0.038	D
Sift4G	Benign	0.071	T
Polyphen		0.33	B
Vest4		0.38
MutPred		0.46		Loss of methylation at K812 (P = 0.0674)
MVP		0.33
MPC		0.35
ClinPred		0.90	D
GERP RS		5.7
Varity_R		0.63
gMVP		0.44
Mutation Taster		=29/71	disease causing

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: rs886041958; hg19: chr14-50612256;