rs11593866

Variant names:

• chr10-111011581-A-T
• rs11593866
• NM_007373.4:c.1541-29A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007373.4(SHOC2):​c.1541-29A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0471 in 1,503,410 control chromosomes in the GnomAD database, including 1,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (330 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1555 hom.)
• Consequence: SHOC2 NM_007373.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.26
• Publications: 1 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: ClinGen, Orphanet
• Noonan syndrome-like disorder with loose anagen hair 1

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 10-111011581-A-T is Benign according to our data. Variant chr10-111011581-A-T is described in ClinVar as Benign. ClinVar VariationId is 260161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOC2	NM_007373.4	c.1541-29A>T		intron_variant	Intron 8 of 8	ENST00000369452.9	NP_031399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOC2	ENST00000369452.9	c.1541-29A>T		intron_variant	Intron 8 of 8	1	NM_007373.4	ENSP00000358464.5

Frequencies

GnomAD3 genomes AF: 0.0587 AC: 8900 AN: 151662 Hom.: 331 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0218

Gnomad FIN AF: 0.0546

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0441

Gnomad OTH AF: 0.0509

GnomAD2 exomes AF: 0.0406 AC: 9768 AN: 240664 AF XY: 0.0396

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0245

Gnomad ASJ exome AF: 0.0808

Gnomad EAS exome AF: 0.00292

Gnomad FIN exome AF: 0.0521

Gnomad NFE exome AF: 0.0421

Gnomad OTH exome AF: 0.0437

GnomAD4 exome AF: 0.0459 AC: 61975 AN: 1351630 Hom.: 1555 Cov.: 24 AF XY: 0.0447 AC XY: 30301 AN XY: 678276

African (AFR) AF: 0.115 AC: 3586 AN: 31298

American (AMR) AF: 0.0261 AC: 1157 AN: 44274

Ashkenazi Jewish (ASJ) AF: 0.0784 AC: 1995 AN: 25436

East Asian (EAS) AF: 0.00231 AC: 90 AN: 39030

South Asian (SAS) AF: 0.0230 AC: 1922 AN: 83728

European-Finnish (FIN) AF: 0.0475 AC: 2376 AN: 49984

Middle Eastern (MID) AF: 0.0585 AC: 325 AN: 5558

European-Non Finnish (NFE) AF: 0.0469 AC: 47624 AN: 1015628

Other (OTH) AF: 0.0512 AC: 2900 AN: 56694

GnomAD4 genome AF: 0.0587 AC: 8903 AN: 151780 Hom.: 330 Cov.: 32 AF XY: 0.0572 AC XY: 4243 AN XY: 74230

African (AFR) AF: 0.106 AC: 4368 AN: 41382

American (AMR) AF: 0.0290 AC: 442 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 279 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5176

South Asian (SAS) AF: 0.0212 AC: 102 AN: 4806

European-Finnish (FIN) AF: 0.0546 AC: 575 AN: 10540

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0441 AC: 2992 AN: 67872

Other (OTH) AF: 0.0508 AC: 107 AN: 2106

Alfa AF: 0.0541 Hom.: 36

Bravo AF: 0.0587

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.0060
DANN	Benign	0.37
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs11593866; hg19: chr10-112771339; COSMIC: COSV99509820;