NM_020975.6:c.2136+182G>A

Variant names:

• chr10-43114918-G-A
• rs1864400
• NM_020975.6:c.2136+182G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020975.6(RET):​c.2136+182G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.824 in 152,028 control chromosomes in the GnomAD database, including 52,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.82 (52197 hom., cov: 30)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.89
• Publications: 14 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 10-43114918-G-A is Benign according to our data. Variant chr10-43114918-G-A is described in ClinVar as Benign. ClinVar VariationId is 1226080.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 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.2136+182G>A		intron	N/A	NP_066124.1
	RET	NM_001406743.1		c.2136+182G>A		intron	N/A	NP_001393672.1
	RET	NM_001406744.1		c.2136+182G>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.2136+182G>A		intron	N/A	ENSP00000347942.3
	RET	ENST00000340058.6	TSL:1	c.2136+182G>A		intron	N/A	ENSP00000344798.4
	RET	ENST00000713926.1		c.1872+182G>A		intron	N/A	ENSP00000519223.1

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125199 AN: 151910 Hom.: 52134 Cov.: 30

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.920

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.814

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.814

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

GnomAD4 genome AF: 0.824 AC: 125326 AN: 152028 Hom.: 52197 Cov.: 30 AF XY: 0.822 AC XY: 61071 AN XY: 74312

African (AFR) AF: 0.908 AC: 37682 AN: 41498

American (AMR) AF: 0.802 AC: 12263 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2664 AN: 3468

East Asian (EAS) AF: 0.497 AC: 2545 AN: 5118

South Asian (SAS) AF: 0.709 AC: 3413 AN: 4814

European-Finnish (FIN) AF: 0.814 AC: 8613 AN: 10582

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.815 AC: 55357 AN: 67944

Other (OTH) AF: 0.814 AC: 1717 AN: 2110

Alfa AF: 0.806 Hom.: 79641

Bravo AF: 0.830

Asia WGS AF: 0.624 AC: 2170 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.26
DANN	Benign	0.35
PhyloP100		-2.9
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: rs1864400; hg19: chr10-43610366; COSMIC: COSV60687565; COSMIC: COSV60687565;