rs2435352

Positions:

• chr10-43105241-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.473

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 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	Protein	UniProt
RET	NM_020975.6	c.867+48A>G		intron_variant		ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.867+48A>G		intron_variant		5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58369 AN: 151506 Hom.: 11499 Cov.: 31

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

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.: 39 AF XY: 0.415 AC XY: 300619 AN XY: 725204

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.: 31 AF XY: 0.388 AC XY: 28775 AN XY: 74070

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 2A Benign:3

Benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 13, 2017	- -
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	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Other links and lift over

dbSNP: rs2435352; hg19: chr10-43600689; COSMIC: COSV60688772; COSMIC: COSV60688772;