chr10-43116778-C-T

Variant names:

• chr10-43116778-C-T
• rs760466
• NM_020975.6:c.2284+47C>T

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.2284+47C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,420,794 control chromosomes in the GnomAD database, including 40,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3404 hom., cov: 31)
  • Exomes 𝑓: 0.23 (37428 hom.)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.973
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-43116778-C-T is Benign according to our data. Variant chr10-43116778-C-T is described in ClinVar as Benign. ClinVar VariationId is 261396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.278 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.2284+47C>T		intron	N/A	NP_066124.1
	RET	NM_001406743.1		c.2284+47C>T		intron	N/A	NP_001393672.1
	RET	NM_001406744.1		c.2284+47C>T		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.2284+47C>T		intron	N/A	ENSP00000347942.3
	RET	ENST00000340058.6	TSL:1	c.2284+47C>T		intron	N/A	ENSP00000344798.4
	RET	ENST00000713926.1		c.2020+47C>T		intron	N/A	ENSP00000519223.1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 28747 AN: 149430 Hom.: 3405 Cov.: 31

Gnomad AFR AF: 0.0576

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.0556

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.154

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.188

GnomAD2 exomes AF: 0.207 AC: 46581 AN: 224580 AF XY: 0.211

Gnomad AFR exome AF: 0.0519

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.248

Gnomad EAS exome AF: 0.0586

Gnomad FIN exome AF: 0.205

Gnomad NFE exome AF: 0.278

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.232 AC: 295438 AN: 1271262 Hom.: 37428 Cov.: 23 AF XY: 0.232 AC XY: 146784 AN XY: 633670

African (AFR) AF: 0.0399 AC: 1233 AN: 30870

American (AMR) AF: 0.186 AC: 6980 AN: 37572

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 5248 AN: 22240

East Asian (EAS) AF: 0.0585 AC: 2185 AN: 37358

South Asian (SAS) AF: 0.135 AC: 10375 AN: 76758

European-Finnish (FIN) AF: 0.198 AC: 9574 AN: 48476

Middle Eastern (MID) AF: 0.135 AC: 522 AN: 3858

European-Non Finnish (NFE) AF: 0.258 AC: 248022 AN: 961594

Other (OTH) AF: 0.215 AC: 11299 AN: 52536

GnomAD4 genome AF: 0.192 AC: 28737 AN: 149532 Hom.: 3404 Cov.: 31 AF XY: 0.187 AC XY: 13598 AN XY: 72910

African (AFR) AF: 0.0574 AC: 2336 AN: 40720

American (AMR) AF: 0.200 AC: 3005 AN: 15026

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 851 AN: 3438

East Asian (EAS) AF: 0.0557 AC: 280 AN: 5026

South Asian (SAS) AF: 0.130 AC: 600 AN: 4620

European-Finnish (FIN) AF: 0.197 AC: 2034 AN: 10318

Middle Eastern (MID) AF: 0.157 AC: 45 AN: 286

European-Non Finnish (NFE) AF: 0.282 AC: 18920 AN: 67144

Other (OTH) AF: 0.186 AC: 383 AN: 2058

Alfa AF: 0.148 Hom.: 447

Bravo AF: 0.188

Asia WGS AF: 0.105 AC: 368 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.38
DANN	Benign	0.87
PhyloP100		-0.97
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: rs760466; hg19: chr10-43612226; COSMIC: COSV60689537;