2-237911609-G-C

Position:

• chr2-237911609-G-C

Variant summary

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

The NM_005855.4(RAMP1):​c.273G>C​(p.Arg91Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAMP1 NM_005855.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.954

Genes affected

RAMP1 (HGNC:9843): (receptor activity modifying protein 1) 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 (RAMP1) protein, CRLR functions as a CGRP receptor. The RAMP1 protein is involved in the terminal glycosylation, maturation, and presentation of the CGRP receptor to the cell surface. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

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=0.14428723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAMP1	NM_005855.4	c.273G>C	p.Arg91Ser	missense_variant	3/3	ENST00000254661.5	NP_005846.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAMP1	ENST00000254661.5	c.273G>C	p.Arg91Ser	missense_variant	3/3	1	NM_005855.4	ENSP00000254661	P1
RAMP1	ENST00000403885.1	c.207G>C	p.Arg69Ser	missense_variant	3/3	3		ENSP00000386046
RAMP1	ENST00000404910.6	c.207G>C	p.Arg69Ser	missense_variant	3/3	2		ENSP00000384688
RAMP1	ENST00000409726.5	c.207G>C	p.Arg69Ser	missense_variant	4/4	3		ENSP00000386720

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2024

The c.273G>C (p.R91S) alteration is located in exon 3 (coding exon 3) of the RAMP1 gene. This alteration results from a G to C substitution at nucleotide position 273, causing the arginine (R) at amino acid position 91 to be replaced by a serine (S). 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	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.048	T;T;T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.83	.;T;.;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.77	T;T;T;T
Sift4G	Benign	0.48	T;T;T;T
Polyphen		0.51	.;P;.;.
Vest4		0.20
MutPred		0.59		.;Loss of MoRF binding (P = 0.1912);.;.;
MVP		0.36
MPC		0.016
ClinPred		0.13	T
GERP RS		0.057
Varity_R		0.42
gMVP		0.51

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: rs773940324; hg19: chr2-238820251;