chr2-54987503-C-G

Position:

• chr2-54987503-C-G

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id is 774406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN4	NM_020532.5	c.3209G>C	p.Gly1070Ala	missense_variant	4/9	ENST00000337526.11	NP_065393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN4	ENST00000337526.11	c.3209G>C	p.Gly1070Ala	missense_variant	4/9	1	NM_020532.5	ENSP00000337838

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

GnomAD3 exomes AF: 0.00255 AC: 639 AN: 251070 Hom.: 3 AF XY: 0.00267 AC XY: 363 AN XY: 135744

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 SAS exome AF: 0.000915

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

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000858

Gnomad4 FIN exome AF: 0.000580

Gnomad4 NFE exome AF: 0.00507

Gnomad4 OTH exome AF: 0.00331

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

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.00284

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

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	RTN4: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

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;.;.;D;D;D;.;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.2	.;.;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;D;D;D;D;.;D
REVEL	Uncertain	0.55
Sift	Benign	0.087	T;D;D;D;T;T;D;D;.;T
Sift4G	Benign	0.17	T;D;D;D;D;D;D;D;T;.
Polyphen		1.0	.;.;.;D;.;D;.;.;.;.
Vest4		0.82
MVP		0.59
MPC		0.24
ClinPred		0.024	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs11549898; hg19: chr2-55214639; COSMIC: COSV105170729;