rs2742234

Variant names:

• chr10-43117161-C-T
• rs2742234
• NM_020975.6:c.2284+430C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020975.6(RET):​c.2284+430C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.763 in 152,222 control chromosomes in the GnomAD database, including 44,714 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.76 (44714 hom., cov: 35)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.56
• Publications: 44 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: G2P, Orphanet
• multiple endocrine neoplasia type 2A

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020975.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.2284+430C>T		intron	N/A	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.2284+430C>T		intron	N/A	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.2284+430C>T		intron	N/A	NP_001393673.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.2284+430C>T		intron	N/A	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.2284+430C>T		intron	N/A	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.2020+430C>T		intron	N/A	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.763 AC: 116086 AN: 152104 Hom.: 44668 Cov.: 35

Gnomad AFR AF: 0.809

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.711

Gnomad EAS AF: 0.496

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.743

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.763 AC: 116193 AN: 152222 Hom.: 44714 Cov.: 35 AF XY: 0.761 AC XY: 56651 AN XY: 74412

African (AFR) AF: 0.809 AC: 33598 AN: 41546

American (AMR) AF: 0.759 AC: 11616 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 2466 AN: 3468

East Asian (EAS) AF: 0.496 AC: 2557 AN: 5154

South Asian (SAS) AF: 0.621 AC: 2995 AN: 4820

European-Finnish (FIN) AF: 0.782 AC: 8297 AN: 10606

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.767 AC: 52133 AN: 68002

Other (OTH) AF: 0.744 AC: 1573 AN: 2114

Alfa AF: 0.761 Hom.: 148726

Bravo AF: 0.767

Asia WGS AF: 0.588 AC: 2046 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.097
DANN	Benign	0.37
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs2742234; hg19: chr10-43612609;