2-54987503-C-G

Variant names:

• chr2-54987503-C-G
• rs11549898
• NM_020532.5:c.3209G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020532.5(RTN4):​c.3209G>C​(p.Gly1070Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,613,038 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (14 hom.)
• Consequence: RTN4 NM_020532.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.91
• Publications: 9 publications found

Genes affected

RTN4 (HGNC:14085): (reticulon 4) This gene belongs to the family of reticulon encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. The product of this gene is a potent neurite outgrowth inhibitor which may also help block the regeneration of the central nervous system in higher vertebrates. Alternatively spliced transcript variants derived both from differential splicing and differential promoter usage and encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013103217).
• BP6: Variant 2-54987503-C-G is Benign according to our data. Variant chr2-54987503-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 774406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020532.5. 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
	RTN4	NM_020532.5	MANE Select	c.3209G>C	p.Gly1070Ala	missense	Exon 4 of 9	NP_065393.1	Q9NQC3-1
	RTN4	NM_001321859.2		c.2591G>C	p.Gly864Ala	missense	Exon 4 of 9	NP_001308788.1	Q9NQC3-6
	RTN4	NM_001321860.1		c.2591G>C	p.Gly864Ala	missense	Exon 4 of 9	NP_001308789.1	Q9NQC3-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN4	ENST00000337526.11	TSL:1 MANE Select	c.3209G>C	p.Gly1070Ala	missense	Exon 4 of 9	ENSP00000337838.6	Q9NQC3-1
	RTN4	ENST00000357376.7	TSL:1	c.2591G>C	p.Gly864Ala	missense	Exon 4 of 9	ENSP00000349944.3	Q9NQC3-6
	RTN4	ENST00000394611.6	TSL:1	c.2591G>C	p.Gly864Ala	missense	Exon 4 of 9	ENSP00000378109.2	Q9NQC3-6

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 152176 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00420

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00255 AC: 639 AN: 251070 AF XY: 0.00267

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00418

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00422 AC: 6171 AN: 1460744 Hom.: 14 Cov.: 33 AF XY: 0.00418 AC XY: 3038 AN XY: 726798

African (AFR) AF: 0.000717 AC: 24 AN: 33460

American (AMR) AF: 0.00174 AC: 78 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 120 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000858 AC: 74 AN: 86250

European-Finnish (FIN) AF: 0.000580 AC: 31 AN: 53412

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5758

European-Non Finnish (NFE) AF: 0.00507 AC: 5635 AN: 1110946

Other (OTH) AF: 0.00331 AC: 200 AN: 60372

GnomAD4 genome AF: 0.00262 AC: 399 AN: 152294 Hom.: 1 Cov.: 33 AF XY: 0.00226 AC XY: 168 AN XY: 74456

African (AFR) AF: 0.00115 AC: 48 AN: 41560

American (AMR) AF: 0.00229 AC: 35 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00422 AC: 287 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00406 Hom.: 2

Bravo AF: 0.00263

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00241 AC: 293

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00391

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.55
Sift	Benign	0.087	T
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.82
MVP		0.59
MPC		0.24
ClinPred		0.024	T
GERP RS		5.7
PromoterAI		-0.0016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.67
Mutation Taster		=75/25	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: rs11549898; hg19: chr2-55214639; COSMIC: COSV105170729;