19-422351-C-G

Variant names:

• chr19-422351-C-G
• rs370591093
• NM_012435.3:c.1415G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012435.3(SHC2):​c.1415G>C​(p.Arg472Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R472Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHC2 NM_012435.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.45
• Publications: 0 publications found

Genes affected

SHC2 (HGNC:29869): (SHC adaptor protein 2) Predicted to enable receptor tyrosine kinase binding activity. Predicted to be involved in transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to be located in cytosol. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3867389).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHC2	NM_012435.3	c.1415G>C	p.Arg472Pro	missense_variant	Exon 11 of 13	ENST00000264554.11	NP_036567.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHC2	ENST00000264554.11	c.1415G>C	p.Arg472Pro	missense_variant	Exon 11 of 13	1	NM_012435.3	ENSP00000264554.4
SHC2	ENST00000588376.5	n.478G>C		non_coding_transcript_exon_variant	Exon 1 of 3	1
SHC2	ENST00000590170.3	n.352G>C		non_coding_transcript_exon_variant	Exon 4 of 6	5		ENSP00000465764.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	0.093
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.24
Sift	Benign	0.039	D
Sift4G	Uncertain	0.018	D
Polyphen		0.014	B
Vest4		0.43
MutPred		0.20		Gain of glycosylation at R472 (P = 0.0231);
MVP		0.83
MPC		0.46
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.73
gMVP		0.61
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370591093; hg19: chr19-422351;