chr10-110964877-G-T

Position:

• chr10-110964877-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_007373.4(SHOC2):​c.519G>T​(p.Met173Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHOC2 NM_007373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SHOC2. . Gene score misZ 2.9666 (greater than the threshold 3.09). Trascript score misZ 3.7843 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome, cardiofaciocutaneous syndrome, Noonan syndrome-like disorder with loose anagen hair 1, Costello syndrome, Noonan syndrome-like disorder with loose anagen hair.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHOC2	NM_007373.4	c.519G>T	p.Met173Ile	missense_variant	2/9	ENST00000369452.9	NP_031399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHOC2	ENST00000369452.9	c.519G>T	p.Met173Ile	missense_variant	2/9	1	NM_007373.4	ENSP00000358464.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 27, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Same amino acid substitution caused by a different nucleotide change (c.519G>A) has been reported in an individual with features consistent with a RASopathy; however, this variant was inherited from an apparently unaffected parent, and functional studies did not conclusively demonstrate a significant effect on protein function (PMID: 25137548); Published functional studies demonstrate that this variant likely results in a gain of function and upregulates ERK pathway by selectively promoting phosphatase complex formation with MRAS and PP1, however results did not conclusively demonstrate a significant effect on protein function compared to wildtype (PMID: 30348783); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31059601, 34553755, 29493581, 35348676, 33526449, 33106373, 32558243, 22670144, 25137548, 30348783, 36175670) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.0022	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.12	N;N;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.27	N;N;N
REVEL	Pathogenic	0.77
Sift	Benign	0.075	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0040	B;B;.
Vest4		0.80
MutPred		0.32		Loss of catalytic residue at M173 (P = 0.0094);Loss of catalytic residue at M173 (P = 0.0094);.;
MVP		0.44
MPC		0.56
ClinPred		0.80	D
GERP RS		4.9
Varity_R		0.21
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs730881020; hg19: chr10-112724635;