14-50150234-G-T

Position:

• chr14-50150234-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000216373.10(SOS2):​c.2162-4C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,561,080 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (18 hom.)
• Consequence: SOS2 ENST00000216373.10 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.003506
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.122

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 14-50150234-G-T is Benign according to our data. Variant chr14-50150234-G-T is described in ClinVar as [Benign]. Clinvar id is 387330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50150234-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00887 (1350/152148) while in subpopulation AFR AF= 0.031 (1288/41504). AF 95% confidence interval is 0.0296. There are 18 homozygotes in gnomad4. There are 627 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1350 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS2	NM_006939.4	c.2162-4C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.2162-4C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006939.4	ENSP00000216373	P1
SOS2	ENST00000543680.5	c.2063-4C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000445328

Frequencies

GnomAD3 genomes AF: 0.00887 AC: 1349 AN: 152030 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

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: 0.000118

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00254 AC: 634 AN: 249596 Hom.: 7 AF XY: 0.00177 AC XY: 239 AN XY: 134908

Gnomad AFR exome AF: 0.0334

Gnomad AMR exome AF: 0.00190

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000662

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00100 AC: 1410 AN: 1408932 Hom.: 18 Cov.: 25 AF XY: 0.000837 AC XY: 589 AN XY: 704046

Gnomad4 AFR exome AF: 0.0332

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000707

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000657

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.00887 AC: 1350 AN: 152148 Hom.: 18 Cov.: 32 AF XY: 0.00843 AC XY: 627 AN XY: 74384

Gnomad4 AFR AF: 0.0310

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00546 Hom.: 3

Bravo AF: 0.0101

Asia WGS AF: 0.00144 AC: 6 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 12, 2017	Variant summary: The SOS2 c.2162-4C>A variant involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 381/121160 control chromosomes from ExAC (including 4 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.033436 (347/10378). This frequency is about 13374 times the estimated maximal expected allele frequency of a pathogenic SOS2 variant (0.0000025), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory in ClinVar has classified this variant as benign. The variant of interest has not, to our knowledge, been reported in literature. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 15, 2020

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.5
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0035
dbscSNV1_RF	Benign	0.040
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: rs57179949; hg19: chr14-50616952;