Variant rs2435352 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020975.6(RET):c.867+48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 1,609,180 control chromosomes in the GnomAD database, including 136,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 11521 hom., cov: 31)

Exomes 𝑓: 0.41 ( 125368 hom. )

Consequence

RET
NM_020975.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.473

Variant links:

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]

RET links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 10-43105241-A-G is Benign according to our data. Variant chr10-43105241-A-G is described in ClinVar as [Benign]. Clinvar id is 261398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6 linkuse as main transcript	c.867+48A>G		intron_variant		ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.867+48A>G		intron_variant		5	NM_020975.6	P4	P07949-1

Frequencies

GnomAD3 genomes

AF:

0.385

AC:

58369

AN:

151506

Hom.:

11499

Cov.:

show subpopulations

Gnomad AFR

AF:

0.304

Gnomad AMI

AF:

0.582

Gnomad AMR

AF:

0.425

Gnomad ASJ

AF:

0.366

Gnomad EAS

AF:

0.433

Gnomad SAS

AF:

0.509

Gnomad FIN

AF:

0.392

Gnomad MID

AF:

0.443

Gnomad NFE

AF:

0.411

Gnomad OTH

AF:

0.386

GnomAD3 exomes

AF:

0.428

AC:

103664

AN:

242328

Hom.:

22572

AF XY:

0.429

AC XY:

56779

AN XY:

132420

show subpopulations

Gnomad AFR exome

AF:

0.302

Gnomad AMR exome

AF:

0.506

Gnomad ASJ exome

AF:

0.369

Gnomad EAS exome

AF:

0.431

Gnomad SAS exome

AF:

0.513

Gnomad FIN exome

AF:

0.386

Gnomad NFE exome

AF:

0.410

Gnomad OTH exome

AF:

0.425

GnomAD4 exome

AF:

0.412

AC:

600877

AN:

1457556

Hom.:

125368

Cov.:

AF XY:

0.415

AC XY:

300619

AN XY:

725204

show subpopulations

Gnomad4 AFR exome

AF:

0.292

Gnomad4 AMR exome

AF:

0.494

Gnomad4 ASJ exome

AF:

0.371

Gnomad4 EAS exome

AF:

0.435

Gnomad4 SAS exome

AF:

0.514

Gnomad4 FIN exome

AF:

0.386

Gnomad4 NFE exome

AF:

0.406

Gnomad4 OTH exome

AF:

0.406

GnomAD4 genome

AF:

0.385

AC:

58433

AN:

151624

Hom.:

11521

Cov.:

AF XY:

0.388

AC XY:

28775

AN XY:

74070

show subpopulations

Gnomad4 AFR

AF:

0.304

Gnomad4 AMR

AF:

0.426

Gnomad4 ASJ

AF:

0.366

Gnomad4 EAS

AF:

0.433

Gnomad4 SAS

AF:

0.509

Gnomad4 FIN

AF:

0.392

Gnomad4 NFE

AF:

0.411

Gnomad4 OTH

AF:

0.390

Alfa

AF:

0.385

Hom.:

2129

Bravo

AF:

0.384

Asia WGS

AF:

0.456

AC:

1588

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia type 2A

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 13, 2017	- -

Multiple endocrine neoplasia type 2B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Pheochromocytoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Multiple endocrine neoplasia, type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

4.3

DANN

Benign

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over