NM_020975.6:c.2284+54C>A

Variant names:

• chr10-43116785-C-A
• rs566375223
• NM_020975.6:c.2284+54C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020975.6(RET):​c.2284+54C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,398,516 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00067 (3 hom., cov: 34)
  • Exomes 𝑓: 0.00038 (5 hom.)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.11
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• familial medullary thyroid carcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hirschsprung disease, susceptibility to, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Haddad syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 10-43116785-C-A is Benign according to our data. Variant chr10-43116785-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220577.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000671 (101/150582) while in subpopulation NFE AF = 0.000311 (21/67460). AF 95% confidence interval is 0.000208. There are 3 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.2284+54C>A		intron_variant	Intron 12 of 19	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.2284+54C>A		intron_variant	Intron 12 of 19	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.000671 AC: 101 AN: 150486 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0220

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000311

Gnomad OTH AF: 0.00145

GnomAD4 exome AF: 0.000377 AC: 471 AN: 1247934 Hom.: 5 AF XY: 0.000358 AC XY: 223 AN XY: 622786

African (AFR) AF: 0.0000337 AC: 1 AN: 29648

American (AMR) AF: 0.0000557 AC: 2 AN: 35938

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 357 AN: 21388

East Asian (EAS) AF: 0.00 AC: 0 AN: 37362

South Asian (SAS) AF: 0.0000258 AC: 2 AN: 77528

European-Finnish (FIN) AF: 0.0000815 AC: 4 AN: 49106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3700

European-Non Finnish (NFE) AF: 0.0000563 AC: 53 AN: 941432

Other (OTH) AF: 0.00100 AC: 52 AN: 51832

GnomAD4 genome AF: 0.000671 AC: 101 AN: 150582 Hom.: 3 Cov.: 34 AF XY: 0.000585 AC XY: 43 AN XY: 73538

African (AFR) AF: 0.00 AC: 0 AN: 41010

American (AMR) AF: 0.00 AC: 0 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.0220 AC: 76 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5088

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000311 AC: 21 AN: 67460

Other (OTH) AF: 0.00144 AC: 3 AN: 2084

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jan 09, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RET: BS1 -

not specified Benign:1

Feb 01, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Multiple endocrine neoplasia type 2A Benign:1

Feb 06, 2018

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Multiple endocrine neoplasia, type 2 Benign:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Sep 21, 2020

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.012
DANN	Benign	0.45
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs566375223; hg19: chr10-43612233; COSMIC: COSV60707833;