chr14-50118856-CA-C

Variant names:

• chr14-50118856-CA-C
• rs10658395
• NM_006939.4:c.3490-4delT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_006939.4(SOS2):​c.3490-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,174,898 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (13 hom.)
• Consequence: SOS2 NM_006939.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.39
• Publications: 4 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: Orphanet, ClinGen
• Noonan syndrome 9

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 14-50118856-CA-C is Benign according to our data. Variant chr14-50118856-CA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 706888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 72 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	NM_006939.4	MANE Select	c.3490-4delT		splice_region intron	N/A	NP_008870.2	Q07890-1
	SOS2	NM_001411020.1		c.3391-4delT		splice_region intron	N/A	NP_001397949.1	Q07890-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	ENST00000216373.10	TSL:1 MANE Select	c.3490-4delT		splice_region intron	N/A	ENSP00000216373.5	Q07890-1
	SOS2	ENST00000543680.5	TSL:1	c.3391-4delT		splice_region intron	N/A	ENSP00000445328.1	Q07890-2
	SOS2	ENST00000934708.1		c.3631-4delT		splice_region intron	N/A	ENSP00000604767.1

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 73 AN: 142682 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000700

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000415

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.000112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00342 AC: 355 AN: 103896 AF XY: 0.00399

Gnomad AFR exome AF: 0.00395

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.00379

Gnomad EAS exome AF: 0.00305

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00129 AC: 1336 AN: 1032128 Hom.: 13 Cov.: 24 AF XY: 0.00149 AC XY: 745 AN XY: 499010

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00134 AC: 32 AN: 23962

American (AMR) AF: 0.000991 AC: 18 AN: 18162

Ashkenazi Jewish (ASJ) AF: 0.000426 AC: 6 AN: 14072

East Asian (EAS) AF: 0.000909 AC: 27 AN: 29700

South Asian (SAS) AF: 0.0190 AC: 625 AN: 32922

European-Finnish (FIN) AF: 0.00126 AC: 45 AN: 35734

Middle Eastern (MID) AF: 0.00170 AC: 7 AN: 4126

European-Non Finnish (NFE) AF: 0.000618 AC: 514 AN: 831394

Other (OTH) AF: 0.00147 AC: 62 AN: 42056

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000504 AC: 72 AN: 142770 Hom.: 0 Cov.: 0 AF XY: 0.000637 AC XY: 44 AN XY: 69026

African (AFR) AF: 0.000211 AC: 8 AN: 37862

American (AMR) AF: 0.0000700 AC: 1 AN: 14294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.000416 AC: 2 AN: 4808

South Asian (SAS) AF: 0.0135 AC: 59 AN: 4368

European-Finnish (FIN) AF: 0.000112 AC: 1 AN: 8924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65990

Other (OTH) AF: 0.00 AC: 0 AN: 1948

Alfa AF: 0.00 Hom.: 761

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Noonan syndrome 9 (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	SOS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10658395; hg19: chr14-50585574;