rs61755579

chr14-50188589-C-Achr14-50188589-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_006939.4(SOS2):c.622G>T(p.Ala208Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000261 in 1,606,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A208T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.15

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17052051).
• BP6: Variant 14-50188589-C-A is Benign according to our data. Variant chr14-50188589-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542398.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS2	NM_006939.4	c.622G>T	p.Ala208Ser	missense_variant	5/23	ENST00000216373.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS2	ENST00000216373.10	c.622G>T	p.Ala208Ser	missense_variant	5/23	1	NM_006939.4	P1
SOS2	ENST00000543680.5	c.622G>T	p.Ala208Ser	missense_variant	5/22	1
SOS2	ENST00000556469.5	n.482-5983G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152060 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000366 AC: 9 AN: 245786 Hom.: 0 AF XY: 0.0000301 AC XY: 4 AN XY: 133054

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000389

Gnomad SAS exome AF: 0.0000676

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000234 AC: 34 AN: 1454784 Hom.: 0 Cov.: 29 AF XY: 0.0000221 AC XY: 16 AN XY: 723930

Gnomad4 AFR exome AF: 0.0000605

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000278

Gnomad4 SAS exome AF: 0.0000704

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152178 Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6 AN XY: 74402

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000682 Hom.: 27

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Noonan syndrome 9 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 17, 2022

Variant summary: SOS2 c.622G>T (p.Ala208Ser) results in a conservative amino acid change located in the Dbl homology (DH) domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 245786 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.622G>T has been reported in the literature as a maternally inherited VUS in an individual affected with pediatric heart disease (example, Reuter_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	0.042
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.40	N;N
REVEL	Benign	0.15
Sift	Benign	0.71	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.056	B;.
Vest4		0.65
MutPred		0.34		Gain of disorder (P = 0.0341);Gain of disorder (P = 0.0341);
MVP		0.63
MPC		0.56
ClinPred		0.14	T
GERP RS		5.6
Varity_R		0.080
gMVP		0.26

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: rs61755579; hg19: chr14-50655307;