chr19-422282-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012435.3(SHC2):​c.1484G>A​(p.Arg495Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,954 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R495W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SHC2
NM_012435.3 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SHC2NM_012435.3 linkc.1484G>A p.Arg495Gln missense_variant Exon 11 of 13 ENST00000264554.11 NP_036567.2 P98077

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SHC2ENST00000264554.11 linkc.1484G>A p.Arg495Gln missense_variant Exon 11 of 13 1 NM_012435.3 ENSP00000264554.4 P98077
SHC2ENST00000588376.5 linkn.547G>A non_coding_transcript_exon_variant Exon 1 of 3 1
SHC2ENST00000590170.3 linkn.*7G>A non_coding_transcript_exon_variant Exon 4 of 6 5 ENSP00000465764.3 K7EKS8
SHC2ENST00000590170.3 linkn.*7G>A 3_prime_UTR_variant Exon 4 of 6 5 ENSP00000465764.3 K7EKS8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459954
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
726248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000312
Hom.:
0
Bravo
AF:
0.00000378
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1484G>A (p.R495Q) alteration is located in exon 11 (coding exon 11) of the SHC2 gene. This alteration results from a G to A substitution at nucleotide position 1484, causing the arginine (R) at amino acid position 495 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Uncertain
0.067
T
BayesDel_noAF
Benign
-0.14
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.60
D
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.19
FATHMM_MKL
Benign
0.46
N
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.38
D
MetaRNN
Uncertain
0.71
D
MetaSVM
Benign
-0.31
T
MutationAssessor
Benign
0.31
N
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-2.3
N
REVEL
Uncertain
0.36
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.019
D
Polyphen
0.24
B
Vest4
0.53
MVP
0.85
MPC
0.41
ClinPred
0.88
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.42
gMVP
0.33

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1270213353; hg19: chr19-422282; API