10-110964369-G-A

Position:

• chr10-110964369-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_007373.4(SHOC2):​c.11G>A​(p.Ser4Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S4R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHOC2 NM_007373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08272663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOC2	NM_007373.4	c.11G>A	p.Ser4Asn	missense_variant	2/9	ENST00000369452.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOC2	ENST00000369452.9	c.11G>A	p.Ser4Asn	missense_variant	2/9	1	NM_007373.4	P1

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

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

SHOC2: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.083	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.76	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.069
Sift	Benign	0.31	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0	B;B
Vest4		0.17
MutPred		0.31		Loss of phosphorylation at S4 (P = 9e-04);Loss of phosphorylation at S4 (P = 9e-04);
MVP		0.20
MPC		0.45
ClinPred		0.50	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.071
gMVP		0.0064

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-112724127;