chr19-418975-C-T

Variant summary

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

The NM_012435.3(SHC2):​c.1702G>A​(p.Ala568Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000296 in 1,585,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

SHC2
NM_012435.3 missense

Scores

3
13
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.31
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.1702G>A p.Ala568Thr missense_variant Exon 12 of 13 ENST00000264554.11 NP_036567.2 P98077
SHC2NM_001387056.1 linkc.1567G>A p.Ala523Thr missense_variant Exon 11 of 12 NP_001373985.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SHC2ENST00000264554.11 linkc.1702G>A p.Ala568Thr missense_variant Exon 12 of 13 1 NM_012435.3 ENSP00000264554.4 P98077

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152234
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000198
AC:
4
AN:
202292
Hom.:
0
AF XY:
0.0000183
AC XY:
2
AN XY:
109554
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000101
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000113
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000251
AC:
36
AN:
1433506
Hom.:
0
Cov.:
30
AF XY:
0.0000253
AC XY:
18
AN XY:
710362
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000979
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:
0.0000255
Gnomad4 OTH exome
AF:
0.0000674
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152352
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74510
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.000457
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000473
Bravo
AF:
0.0000831
ExAC
AF:
0.0000250
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 25, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1702G>A (p.A568T) alteration is located in exon 12 (coding exon 12) of the SHC2 gene. This alteration results from a G to A substitution at nucleotide position 1702, causing the alanine (A) at amino acid position 568 to be replaced by a threonine (T). 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
Pathogenic
0.61
BayesDel_addAF
Uncertain
0.064
T
BayesDel_noAF
Benign
-0.15
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.78
D
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
M_CAP
Uncertain
0.13
D
MetaRNN
Uncertain
0.69
D
MetaSVM
Uncertain
-0.21
T
MutationAssessor
Uncertain
2.6
M
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-2.4
N
REVEL
Benign
0.24
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0050
D
Polyphen
1.0
D
Vest4
0.75
MutPred
0.31
Loss of loop (P = 0.2237);
MVP
0.86
MPC
0.40
ClinPred
0.92
D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.36
gMVP
0.28

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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: rs200038781; hg19: chr19-418975; API