rs144391749

chr14-50134116-G-A

Variant summary

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

The NM_006939.4(SOS2):c.3075+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00972 in 1,309,156 control chromosomes in the GnomAD database, including 84 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 0.0075 (2 hom., cov: 32)
  • Exomes 𝑓: 0.010 (82 hom.)
• Consequence: SOS2 NM_006939.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001460
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.276

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=-0.74).
• BP6: Variant 14-50134116-G-A is Benign according to our data. Variant chr14-50134116-G-A is described in ClinVar as [Benign]. Clinvar id is 384712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50134116-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.01 (11588/1156932) while in subpopulation MID AF= 0.0228 (118/5184). AF 95% confidence interval is 0.0194. There are 82 homozygotes in gnomad4_exome. There are 5895 alleles in male gnomad4_exome subpopulation. Median coverage is 16. This position pass quality control queck.
• BS2: High AC in GnomAd at 1139 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS2	NM_006939.4	c.3075+7C>T		splice_region_variant, intron_variant		ENST00000216373.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS2	ENST00000216373.10	c.3075+7C>T		splice_region_variant, intron_variant		1	NM_006939.4	P1
SOS2	ENST00000543680.5	c.2976+7C>T		splice_region_variant, intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00749 AC: 1139 AN: 152106 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.00623

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00849 AC: 2070 AN: 243826 Hom.: 13 AF XY: 0.00905 AC XY: 1190 AN XY: 131508

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00753

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.0000555

Gnomad SAS exome AF: 0.00614

Gnomad FIN exome AF: 0.00815

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0120

GnomAD4 exome AF: 0.0100 AC: 11588 AN: 1156932 Hom.: 82 Cov.: 16 AF XY: 0.00999 AC XY: 5895 AN XY: 590082

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00824

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00718

Gnomad4 FIN exome AF: 0.00794

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00748 AC: 1138 AN: 152224 Hom.: 2 Cov.: 32 AF XY: 0.00724 AC XY: 539 AN XY: 74426

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.00623

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0106 Hom.: 6

Bravo AF: 0.00792

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0128

EpiControl AF: 0.0141

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2016	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	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SOS2: BP4, BS1, BS2 -
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.3075+7C>T variant involves the alteration of a non-conserved intronic nucleotide. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 1055/121182 control chromosomes (including 7 homozygotes) from ExAC, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.011545 (770/66694). This frequency is about 4618 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 European (Non-Finnish) origin. One clinical diagnostic laboratory 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. -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.99
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0080
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: rs144391749; hg19: chr14-50600834;