rs16868675

Variant names:

• chr5-16481076-A-G
• rs16868675
• NM_001034850.3:c.603T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001034850.3(RETREG1):​c.603T>C​(p.Cys201Cys) variant causes a synonymous change. The variant allele was found at a frequency of 0.0285 in 1,610,944 control chromosomes in the GnomAD database, including 2,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (1056 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1233 hom.)
• Consequence: RETREG1 NM_001034850.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.08
• Publications: 9 publications found

Genes affected

RETREG1 (HGNC:25964): (reticulophagy regulator 1) The protein encoded by this gene is a cis-Golgi transmembrane protein that may be necessary for the long-term survival of nociceptive and autonomic ganglion neurons. Mutations in this gene are a cause of hereditary sensory and autonomic neuropathy type IIB (HSAN IIB), and this gene may also play a role in susceptibility to vascular dementia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

RETREG1 Gene-Disease associations (from GenCC):

• neuropathy, hereditary sensory and autonomic, type 2B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 5-16481076-A-G is Benign according to our data. Variant chr5-16481076-A-G is described in ClinVar as Benign. ClinVar VariationId is 137274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RETREG1	NM_001034850.3	c.603T>C	p.Cys201Cys	synonymous_variant	Exon 5 of 9	ENST00000306320.10	NP_001030022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RETREG1	ENST00000306320.10	c.603T>C	p.Cys201Cys	synonymous_variant	Exon 5 of 9	1	NM_001034850.3	ENSP00000304642.9

Frequencies

GnomAD3 genomes AF: 0.0754 AC: 11460 AN: 152040 Hom.: 1044 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00536

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0622

GnomAD2 exomes AF: 0.0284 AC: 7045 AN: 248430 AF XY: 0.0247

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.00367

Gnomad FIN exome AF: 0.00606

Gnomad NFE exome AF: 0.0205

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0236 AC: 34470 AN: 1458786 Hom.: 1233 Cov.: 30 AF XY: 0.0224 AC XY: 16224 AN XY: 725836

African (AFR) AF: 0.229 AC: 7628 AN: 33310

American (AMR) AF: 0.0204 AC: 910 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 316 AN: 26042

East Asian (EAS) AF: 0.00462 AC: 183 AN: 39634

South Asian (SAS) AF: 0.00501 AC: 432 AN: 86216

European-Finnish (FIN) AF: 0.00709 AC: 378 AN: 53294

Middle Eastern (MID) AF: 0.0259 AC: 149 AN: 5750

European-Non Finnish (NFE) AF: 0.0204 AC: 22622 AN: 1109716

Other (OTH) AF: 0.0307 AC: 1852 AN: 60242

GnomAD4 genome AF: 0.0757 AC: 11514 AN: 152158 Hom.: 1056 Cov.: 32 AF XY: 0.0730 AC XY: 5435 AN XY: 74412

African (AFR) AF: 0.224 AC: 9311 AN: 41486

American (AMR) AF: 0.0331 AC: 505 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00866 AC: 30 AN: 3466

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5184

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4824

European-Finnish (FIN) AF: 0.00536 AC: 57 AN: 10626

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1432 AN: 67978

Other (OTH) AF: 0.0616 AC: 130 AN: 2112

Alfa AF: 0.0396 Hom.: 588

Bravo AF: 0.0841

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.0205

EpiControl AF: 0.0199

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 06, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Neuropathy, hereditary sensory and autonomic, type 2B Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.66
PhyloP100		5.1
Mutation Taster		=76/24	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: rs16868675; hg19: chr5-16481185; COSMIC: COSV104626867;