rs994413267

Variant names:

• chr17-42761280-G-C
• rs994413267
• NM_005854.3:c.19G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005854.3(RAMP2):​c.19G>C​(p.Glu7Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000726 in 1,240,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000073 (0 hom.)
• Consequence: RAMP2 NM_005854.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

Genes affected

RAMP2 (HGNC:9844): (receptor activity modifying protein 2) The protein encoded by this gene is a member of the RAMP family of single-transmembrane-domain proteins, called receptor (calcitonin) activity modifying proteins (RAMPs). RAMPs are type I transmembrane proteins with an extracellular N terminus and a cytoplasmic C terminus. RAMPs are required to transport calcitonin-receptor-like receptor (CRLR) to the plasma membrane. CRLR, a receptor with seven transmembrane domains, can function as either a calcitonin-gene-related peptide (CGRP) receptor or an adrenomedullin receptor, depending on which members of the RAMP family are expressed. In the presence of this (RAMP2) protein, CRLR functions as an adrenomedullin receptor. The RAMP2 protein is involved in core glycosylation and transportation of adrenomedullin receptor to the cell surface. [provided by RefSeq, Jul 2008]

RAMP2-AS1 (HGNC:44358): (RAMP2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16270068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAMP2	NM_005854.3	c.19G>C	p.Glu7Gln	missense_variant	Exon 1 of 4	ENST00000253796.10	NP_005845.2
RAMP2-AS1	NR_024461.1	n.-23C>G		upstream_gene_variant
RAMP2-AS1	NR_024462.1	n.-23C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAMP2	ENST00000253796.10	c.19G>C	p.Glu7Gln	missense_variant	Exon 1 of 4	1	NM_005854.3	ENSP00000253796.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000726 AC: 9 AN: 1240512 Hom.: 0 Cov.: 29 AF XY: 0.00000658 AC XY: 4 AN XY: 607810

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000373

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.92e-7

Gnomad4 OTH exome AF: 0.000138

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19G>C (p.E7Q) alteration is located in exon 1 (coding exon 1) of the RAMP2 gene. This alteration results from a G to C substitution at nucleotide position 19, causing the glutamic acid (E) at amino acid position 7 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.16	T;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.0	M;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.10	N;.;.
REVEL	Benign	0.043
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.33	B;.;.
Vest4		0.26
MutPred		0.28		Loss of methylation at R5 (P = 0.0807);Loss of methylation at R5 (P = 0.0807);Loss of methylation at R5 (P = 0.0807);
MVP		0.67
MPC		0.64
ClinPred		0.59	D
GERP RS		1.7
Varity_R		0.27
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs994413267; hg19: chr17-40913298;