Genetic Variant SHOC2:c.1541-7dupT (chr10-111011593-A-AT) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_007373.4(SHOC2):c.1541-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,530,892 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00092 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 2 hom. )

Consequence

SHOC2
NM_007373.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.46

Publications

0 publications found

Variant links:

Genes affected

SHOC2 (HGNC:15454): (SHOC2 leucine rich repeat scaffold protein) This gene encodes a protein that consists almost entirely of leucine-rich repeats, a domain implicated in protein-protein interactions. The protein may function as a scaffold linking RAS to downstream signal transducers in the RAS/ERK MAP kinase signaling cascade. Mutations in this gene have been associated with Noonan-like syndrome with loose anagen hair. [provided by RefSeq, May 2010]

SHOC2 Gene-Disease associations (from GenCC):

Noonan syndrome-like disorder with loose anagen hair
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Noonan syndrome-like disorder with loose anagen hair 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, PanelApp Australia
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SHOC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP6

Variant 10-111011593-A-AT is Benign according to our data. Variant chr10-111011593-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 139 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007373.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SHOC2	NM_007373.4	MANE Select	c.1541-7dupT	splice_region intron	N/A	NP_031399.2
SHOC2	NM_001324336.2		c.1541-7dupT	splice_region intron	N/A	NP_001311265.1	Q9UQ13-1
SHOC2	NM_001324337.2		c.1541-7dupT	splice_region intron	N/A	NP_001311266.1	Q9UQ13-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SHOC2	ENST00000369452.9	TSL:1 MANE Select	c.1541-17_1541-16insT	intron	N/A	ENSP00000358464.5	Q9UQ13-1
SHOC2	ENST00000685059.1		c.1541-17_1541-16insT	intron	N/A	ENSP00000510210.1	Q9UQ13-1
SHOC2	ENST00000688928.1		c.1541-17_1541-16insT	intron	N/A	ENSP00000509273.1	Q9UQ13-1

Frequencies

GnomAD3 genomes

AF:

0.000915

AC:

138

AN:

150754

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000927

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000418

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000488

Gnomad OTH

AF:

0.000964

GnomAD2 exomes

AF:

0.000813

AC:

182

AN:

223736

AF XY:

0.000775

show subpopulations

Gnomad AFR exome

AF:

0.00242

Gnomad AMR exome

AF:

0.000605

Gnomad ASJ exome

AF:

0.000221

Gnomad EAS exome

AF:

0.000119

Gnomad FIN exome

AF:

0.00109

Gnomad NFE exome

AF:

0.000696

Gnomad OTH exome

AF:

0.00183

GnomAD4 exome

AF:

0.00130

AC:

1794

AN:

1380020

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

845

AN XY:

689612

show subpopulations

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

African (AFR)

AF:

0.00297

AC:

AN:

31602

American (AMR)

AF:

0.000685

AC:

AN:

43814

Ashkenazi Jewish (ASJ)

AF:

0.000358

AC:

AN:

25174

East Asian (EAS)

AF:

0.000233

AC:

AN:

38696

South Asian (SAS)

AF:

0.000881

AC:

AN:

84002

European-Finnish (FIN)

AF:

0.000473

AC:

AN:

50730

Middle Eastern (MID)

AF:

0.00467

AC:

AN:

5564

European-Non Finnish (NFE)

AF:

0.00138

AC:

1441

AN:

1042910

Other (OTH)

AF:

0.00151

AC:

AN:

57528

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.346

Heterozygous variant carriers

166

332

497

663

829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000921

AC:

139

AN:

150872

Hom.:

Cov.:

AF XY:

0.000964

AC XY:

AN XY:

73688

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

41142

American (AMR)

AF:

0.000926

AC:

AN:

15122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.000419

AC:

AN:

4776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000489

AC:

AN:

67546

Other (OTH)

AF:

0.000954

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000914

Hom.:

Asia WGS

AF:

0.00144

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Noonan syndrome and Noonan-related syndrome (1)

not provided (1)

not specified (1)

RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

10-111011593-ATT-ATTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over