10-111011593-ATT-AT

Variant names:

• chr10-111011593-AT-A
• rs371544139
• NM_007373.4:c.1541-7delT

Variant summary

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

The NM_007373.4(SHOC2):​c.1541-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00728 in 1,533,536 control chromosomes in the GnomAD database, including 63 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 0.0060 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (54 hom.)
• Consequence: SHOC2 NM_007373.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.46
• Publications: 0 publications found

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

ACMG classification

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

• BP6: Variant 10-111011593-AT-A is Benign according to our data. Variant chr10-111011593-AT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 928786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 912 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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 911 AN: 150756 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00503

Gnomad ASJ AF: 0.000869

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00705

Gnomad OTH AF: 0.00530

GnomAD2 exomes AF: 0.00704 AC: 1575 AN: 223736 AF XY: 0.00700

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000662

Gnomad EAS exome AF: 0.000356

Gnomad FIN exome AF: 0.0337

Gnomad NFE exome AF: 0.00836

Gnomad OTH exome AF: 0.00714

GnomAD4 exome AF: 0.00741 AC: 10251 AN: 1382662 Hom.: 54 Cov.: 28 AF XY: 0.00705 AC XY: 4872 AN XY: 690804

African (AFR) AF: 0.00155 AC: 49 AN: 31652

American (AMR) AF: 0.00194 AC: 85 AN: 43820

Ashkenazi Jewish (ASJ) AF: 0.000556 AC: 14 AN: 25190

East Asian (EAS) AF: 0.0000517 AC: 2 AN: 38696

South Asian (SAS) AF: 0.000190 AC: 16 AN: 84086

European-Finnish (FIN) AF: 0.0278 AC: 1408 AN: 50726

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5566

European-Non Finnish (NFE) AF: 0.00794 AC: 8301 AN: 1045392

Other (OTH) AF: 0.00652 AC: 375 AN: 57534

GnomAD4 genome AF: 0.00604 AC: 912 AN: 150874 Hom.: 9 Cov.: 32 AF XY: 0.00695 AC XY: 512 AN XY: 73694

African (AFR) AF: 0.00107 AC: 44 AN: 41142

American (AMR) AF: 0.00503 AC: 76 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.000869 AC: 3 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4776

European-Finnish (FIN) AF: 0.0290 AC: 301 AN: 10384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00706 AC: 477 AN: 67544

Other (OTH) AF: 0.00525 AC: 11 AN: 2096

Alfa AF: 0.00354 Hom.: 0

Bravo AF: 0.00446

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	Noonan syndrome-like disorder with loose anagen hair 1 (1)
-	-	1	RASopathy (1)
-	-	1	SHOC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs371544139; hg19: chr10-112771351;