chr19-422282-C-G

Variant names:

• chr19-422282-C-G
• rs1270213353
• NM_012435.3:c.1484G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012435.3(SHC2):​c.1484G>C​(p.Arg495Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R495Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SHC2 NM_012435.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012435.3. 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
	SHC2	NM_012435.3	MANE Select	c.1484G>C	p.Arg495Pro	missense	Exon 11 of 13	NP_036567.2	P98077
	SHC2	NM_001387056.1		c.1349G>C	p.Arg450Pro	missense	Exon 10 of 12	NP_001373985.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHC2	ENST00000264554.11	TSL:1 MANE Select	c.1484G>C	p.Arg495Pro	missense	Exon 11 of 13	ENSP00000264554.4	P98077
	SHC2	ENST00000588376.5	TSL:1	n.547G>C		non_coding_transcript_exon	Exon 1 of 3
	SHC2	ENST00000945174.1		c.1562G>C	p.Arg521Pro	missense	Exon 12 of 14	ENSP00000615233.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459954 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726248

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111610

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.055	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.31	B
Vest4		0.68
MutPred		0.53		Loss of MoRF binding (P = 0.018)
MVP		0.91
MPC		0.48
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.91
gMVP		0.80
Mutation Taster		=67/33	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: rs1270213353; hg19: chr19-422282;