rs2251674

Variant names:

• chr10-43109944-G-A
• rs2251674
• NM_020975.6:c.1263+714G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-43109944-G-A
• chr10-43109944-G-C

Variant summary

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

The NM_020975.6(RET):​c.1263+714G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 152,120 control chromosomes in the GnomAD database, including 44,232 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 (44232 hom., cov: 33)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.847 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.1263+714G>A		intron	N/A	NP_066124.1
	RET	NM_001406743.1		c.1263+714G>A		intron	N/A	NP_001393672.1
	RET	NM_001406744.1		c.1263+714G>A		intron	N/A	NP_001393673.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.1263+714G>A		intron	N/A	ENSP00000347942.3
	RET	ENST00000340058.6	TSL:1	c.1263+714G>A		intron	N/A	ENSP00000344798.4
	RET	ENST00000713926.1		c.1134+714G>A		intron	N/A	ENSP00000519223.1

Frequencies

GnomAD3 genomes AF: 0.758 AC: 115199 AN: 152002 Hom.: 44179 Cov.: 33

Gnomad AFR AF: 0.854

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.711

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.748

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

GnomAD4 genome AF: 0.758 AC: 115316 AN: 152120 Hom.: 44232 Cov.: 33 AF XY: 0.752 AC XY: 55897 AN XY: 74348

African (AFR) AF: 0.854 AC: 35473 AN: 41524

American (AMR) AF: 0.749 AC: 11456 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 2467 AN: 3472

East Asian (EAS) AF: 0.543 AC: 2810 AN: 5174

South Asian (SAS) AF: 0.709 AC: 3417 AN: 4822

European-Finnish (FIN) AF: 0.636 AC: 6710 AN: 10558

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.742 AC: 50435 AN: 67972

Other (OTH) AF: 0.748 AC: 1576 AN: 2108

Alfa AF: 0.751 Hom.: 16249

Bravo AF: 0.772

Asia WGS AF: 0.638 AC: 2222 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.48
DANN	Benign	0.58
PhyloP100		-1.3
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: rs2251674; hg19: chr10-43605392; COSMIC: COSV60686041;