2-237859694-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001308353.2(RAMP1):​c.-109C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,360,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

RAMP1
NM_001308353.2 5_prime_UTR_premature_start_codon_gain

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0250
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.14022377).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAMP1NM_005855.4 linkc.19C>T p.Arg7Cys missense_variant Exon 1 of 3 ENST00000254661.5 NP_005846.1 O60894

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAMP1ENST00000254661.5 linkc.19C>T p.Arg7Cys missense_variant Exon 1 of 3 1 NM_005855.4 ENSP00000254661.4 O60894
RAMP1ENST00000409726 linkc.-109C>T 5_prime_UTR_premature_start_codon_gain_variant Exon 1 of 4 3 ENSP00000386720.1 E9PC20
RAMP1ENST00000409726 linkc.-109C>T 5_prime_UTR_variant Exon 1 of 4 3 ENSP00000386720.1 E9PC20
RAMP1ENST00000404910.6 linkc.-15+567C>T intron_variant Intron 1 of 2 2 ENSP00000384688.2 E9PC20

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.35e-7
AC:
1
AN:
1360212
Hom.:
0
Cov.:
31
AF XY:
0.00000149
AC XY:
1
AN XY:
670396
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.41e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 04, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.19C>T (p.R7C) alteration is located in exon 1 (coding exon 1) of the RAMP1 gene. This alteration results from a C to T substitution at nucleotide position 19, causing the arginine (R) at amino acid position 7 to be replaced by a cysteine (C). 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
-0.27
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Benign
0.22
T
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.94
FATHMM_MKL
Benign
0.033
N
LIST_S2
Benign
0.67
T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.14
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.10
Sift
Benign
0.10
T
Sift4G
Benign
0.11
T
Polyphen
0.99
D
Vest4
0.077
MutPred
0.33
Loss of MoRF binding (P = 3e-04);
MVP
0.39
MPC
0.021
ClinPred
0.41
T
GERP RS
1.3
Varity_R
0.083
gMVP
0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-238768337; API