rs373143128

chr14-50145232-C-Achr14-50145232-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006939.4(SOS2):c.2605G>T(p.Val869Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,610,340 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V869A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS2	NM_006939.4	c.2605G>T	p.Val869Leu	missense_variant	16/23	ENST00000216373.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS2	ENST00000216373.10	c.2605G>T	p.Val869Leu	missense_variant	16/23	1	NM_006939.4	P1
SOS2	ENST00000543680.5	c.2506G>T	p.Val836Leu	missense_variant	15/22	1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251052 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135718

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458286 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74270

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.0097	T
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.24	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.13
Sift	Benign	0.27	T;T
Sift4G	Benign	0.087	T;T
Polyphen		0.0090	B;.
Vest4		0.82
MutPred		0.54		Loss of helix (P = 0.3949);.;
MVP		0.33
MPC		0.34
ClinPred		0.58	D
GERP RS		4.7
Varity_R		0.54
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs373143128; hg19: chr14-50611950;