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:5
• 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):

• hereditary sensory and autonomic neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034850.3. 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
	RETREG1	NM_001034850.3	MANE Select	c.603T>C	p.Cys201Cys	synonymous	Exon 5 of 9	NP_001030022.1	Q9H6L5-1
	RETREG1	NM_019000.5		c.180T>C	p.Cys60Cys	synonymous	Exon 3 of 7	NP_061873.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.603T>C	p.Cys201Cys	synonymous	Exon 5 of 9	ENSP00000304642.9	Q9H6L5-1
	RETREG1	ENST00000399793.6	TSL:1	c.180T>C	p.Cys60Cys	synonymous	Exon 3 of 7	ENSP00000382691.2	Q9H6L5-2
	RETREG1	ENST00000510362.6	TSL:1	n.78T>C		non_coding_transcript_exon	Exon 3 of 8	ENSP00000425089.2	H0Y9U4

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Neuropathy, hereditary sensory and autonomic, type 2B (1)

Computational scores

Source: dbNSFP v4.9

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;