rs2435352

Variant names:

• chr10-43105241-A-G
• rs2435352
• NM_020975.6:c.867+48A>G

Variant summary

Our verdict is Benign. The variant received -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:9
• Conservation: PhyloP100: -0.473
• Publications: 15 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 -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 VariationId 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.

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.867+48A>G		intron	N/A	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.867+48A>G		intron	N/A	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.867+48A>G		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.867+48A>G		intron	N/A	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.867+48A>G		intron	N/A	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.738+48A>G		intron	N/A	ENSP00000519223.1	A0AAQ5BH28

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

GnomAD2 exomes AF: 0.428 AC: 103664 AN: 242328 AF XY: 0.429

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 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

African (AFR) AF: 0.292 AC: 9762 AN: 33416

American (AMR) AF: 0.494 AC: 22010 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 9691 AN: 26090

East Asian (EAS) AF: 0.435 AC: 17239 AN: 39630

South Asian (SAS) AF: 0.514 AC: 44252 AN: 86126

European-Finnish (FIN) AF: 0.386 AC: 19535 AN: 50630

Middle Eastern (MID) AF: 0.426 AC: 2424 AN: 5694

European-Non Finnish (NFE) AF: 0.406 AC: 451489 AN: 1111062

Other (OTH) AF: 0.406 AC: 24475 AN: 60312

GnomAD4 genome AF: 0.385 AC: 58433 AN: 151624 Hom.: 11521 Cov.: 31 AF XY: 0.388 AC XY: 28775 AN XY: 74070

African (AFR) AF: 0.304 AC: 12559 AN: 41334

American (AMR) AF: 0.426 AC: 6500 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1270 AN: 3470

East Asian (EAS) AF: 0.433 AC: 2204 AN: 5092

South Asian (SAS) AF: 0.509 AC: 2442 AN: 4794

European-Finnish (FIN) AF: 0.392 AC: 4131 AN: 10530

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.411 AC: 27848 AN: 67834

Other (OTH) AF: 0.390 AC: 818 AN: 2098

Alfa AF: 0.383 Hom.: 2172

Bravo AF: 0.384

Asia WGS AF: 0.456 AC: 1588 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Multiple endocrine neoplasia type 2A (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Multiple endocrine neoplasia type 2B (1)
-	-	1	Multiple endocrine neoplasia, type 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Pheochromocytoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.29
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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