chr19-422282-C-T

Variant names:

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

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

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

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
SHC2	NM_012435.3	c.1484G>A	p.Arg495Gln	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.1484G>A	p.Arg495Gln	missense_variant	Exon 11 of 13	1	NM_012435.3	ENSP00000264554.4
SHC2	ENST00000588376.5	n.547G>A		non_coding_transcript_exon_variant	Exon 1 of 3	1
SHC2	ENST00000590170.3	n.*7G>A		non_coding_transcript_exon_variant	Exon 4 of 6	5		ENSP00000465764.3
SHC2	ENST00000590170.3	n.*7G>A		3_prime_UTR_variant	Exon 4 of 6	5		ENSP00000465764.3

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

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

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

Other links and lift over

dbSNP: rs1270213353; hg19: chr19-422282;