chr2-86216945-A-G

Variant names:

• chr2-86216945-A-G
• rs141976852
• NM_001371279.1:c.*94T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001371279.1(REEP1):​c.*94T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,019,268 control chromosomes in the GnomAD database, including 506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.022 (69 hom., cov: 32)
  • Exomes 𝑓: 0.028 (437 hom.)
• Consequence: REEP1 NM_001371279.1 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.36
• Publications: 3 publications found

Genes affected

REEP1 (HGNC:25786): (receptor accessory protein 1) This gene encodes a mitochondrial protein that functions to enhance the cell surface expression of odorant receptors. Mutations in this gene cause spastic paraplegia autosomal dominant type 31, a neurodegenerative disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

REEP1 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 31

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• neuronopathy, distal hereditary motor, type 5B

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• neuronopathy, distal hereditary motor, type 5A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• spinal muscular atrophy, distal, autosomal recessive, 6

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-86216945-A-G is Benign according to our data. Variant chr2-86216945-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 337385.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0218 (3318/152272) while in subpopulation NFE AF = 0.0336 (2286/68022). AF 95% confidence interval is 0.0325. There are 69 homozygotes in GnomAd4. There are 1577 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 69 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371279.1. 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
	REEP1	NM_001371279.1	MANE Select	c.*94T>C		3_prime_UTR	Exon 9 of 9	NP_001358208.1	A0A1C7CYY3
	REEP1	NM_001410855.1		c.*94T>C		3_prime_UTR	Exon 8 of 8	NP_001397784.1	A0A2R8Y6K6
	REEP1	NM_001410856.1		c.*155T>C		3_prime_UTR	Exon 8 of 8	NP_001397785.1	A0A8I5QKJ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REEP1	ENST00000538924.7	TSL:5 MANE Select	c.*94T>C		3_prime_UTR	Exon 9 of 9	ENSP00000438346.3	A0A1C7CYY3
	REEP1	ENST00000165698.9	TSL:1	c.*155T>C		3_prime_UTR	Exon 7 of 7	ENSP00000165698.5	Q9H902-1
	REEP1	ENST00000908467.1		c.*94T>C		3_prime_UTR	Exon 9 of 9	ENSP00000578526.1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3318 AN: 152154 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.00596

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0336

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.0278 AC: 24094 AN: 866996 Hom.: 437 Cov.: 12 AF XY: 0.0270 AC XY: 12115 AN XY: 448970

African (AFR) AF: 0.00575 AC: 124 AN: 21562

American (AMR) AF: 0.0118 AC: 443 AN: 37476

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 263 AN: 21626

East Asian (EAS) AF: 0.0000286 AC: 1 AN: 34964

South Asian (SAS) AF: 0.00234 AC: 163 AN: 69704

European-Finnish (FIN) AF: 0.0357 AC: 1800 AN: 50470

Middle Eastern (MID) AF: 0.00951 AC: 43 AN: 4520

European-Non Finnish (NFE) AF: 0.0347 AC: 20322 AN: 586004

Other (OTH) AF: 0.0230 AC: 935 AN: 40670

GnomAD4 genome AF: 0.0218 AC: 3318 AN: 152272 Hom.: 69 Cov.: 32 AF XY: 0.0212 AC XY: 1577 AN XY: 74470

African (AFR) AF: 0.00595 AC: 247 AN: 41542

American (AMR) AF: 0.0161 AC: 247 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4824

European-Finnish (FIN) AF: 0.0332 AC: 352 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0336 AC: 2286 AN: 68022

Other (OTH) AF: 0.0204 AC: 43 AN: 2112

Alfa AF: 0.0303 Hom.: 29

Bravo AF: 0.0198

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 31 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.83
PhyloP100		3.4
Mutation Taster		=100/0	polymorphism

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: rs141976852; hg19: chr2-86444068;