rs786201522

Positions:

• chr10-43102608-G-C
• chr10-43102608-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_020975.6(RET):​c.604G>C​(p.Val202Leu) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.81

Genes affected

RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-43102608-G-C is Pathogenic according to our data. Variant chr10-43102608-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 599632.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.352799). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.604G>C	p.Val202Leu	missense_variant	3/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.604G>C	p.Val202Leu	missense_variant	3/20	5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Aganglionic megacolon Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Human Genomics Unit, Institute for molecular medicine Finland (FIMM)

Jan 01, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.39	T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M;.;M
MutationTaster	Benign	0.97	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N;.;N
REVEL	Benign	0.034
Sift	Benign	0.059	T;.;T
Sift4G	Uncertain	0.035	D;T;D
Polyphen		0.056	B;.;B
Vest4		0.30
MutPred		0.73		Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);
MVP		0.52
MPC		0.89
ClinPred		0.36	T
GERP RS		1.6
Varity_R		0.14
gMVP		0.61

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: rs751572082; hg19: chr10-43598056;