14-50157042-G-A

Variant names:

• chr14-50157042-G-A
• rs34139502
• NM_006939.4:c.2014C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006939.4(SOS2):​c.2014C>T​(p.Leu672Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L672I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.89
• 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3848157).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	NM_006939.4	MANE Select	c.2014C>T	p.Leu672Phe	missense	Exon 12 of 23	NP_008870.2
	SOS2	NM_001411020.1		c.1915C>T	p.Leu639Phe	missense	Exon 11 of 22	NP_001397949.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	ENST00000216373.10	TSL:1 MANE Select	c.2014C>T	p.Leu672Phe	missense	Exon 12 of 23	ENSP00000216373.5
	SOS2	ENST00000543680.5	TSL:1	c.1915C>T	p.Leu639Phe	missense	Exon 11 of 22	ENSP00000445328.1
	SOS2	ENST00000555794.2	TSL:1	c.1126C>T	p.Leu376Phe	missense	Exon 6 of 6	ENSP00000484766.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459944 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726246

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110886

Other (OTH) AF: 0.00 AC: 0 AN: 60282

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.095
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.089
Sift	Benign	0.17	T
Sift4G	Benign	0.095	T
Polyphen		0.045	B
Vest4		0.62
MutPred		0.47		Gain of methylation at K673 (P = 0.0296)
MVP		0.26
MPC		1.6
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.55
gMVP		0.68
Mutation Taster		=33/67	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: rs34139502; hg19: chr14-50623760;