NM_005855.4:c.19C>T

Variant names:

• chr2-237859694-C-T
• NM_005855.4:c.19C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005855.4(RAMP1):​c.19C>T​(p.Arg7Cys) variant causes a missense 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. 14/22 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)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: RAMP1 NM_005855.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0250
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14022377).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005855.4. 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
	RAMP1	NM_005855.4	MANE Select	c.19C>T	p.Arg7Cys	missense	Exon 1 of 3	NP_005846.1	O60894
	RAMP1	NM_001308353.2		c.-109C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_001295282.1	E9PC20
	RAMP1	NM_001308353.2		c.-109C>T		5_prime_UTR	Exon 1 of 4	NP_001295282.1	E9PC20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAMP1	ENST00000254661.5	TSL:1 MANE Select	c.19C>T	p.Arg7Cys	missense	Exon 1 of 3	ENSP00000254661.4	O60894
	RAMP1	ENST00000409726.5	TSL:3	c.-109C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000386720.1	E9PC20
	RAMP1	ENST00000884471.1		c.19C>T	p.Arg7Cys	missense	Exon 1 of 5	ENSP00000554530.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27716

American (AMR) AF: 0.00 AC: 0 AN: 31848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24050

East Asian (EAS) AF: 0.00 AC: 0 AN: 30986

South Asian (SAS) AF: 0.00 AC: 0 AN: 75056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3984

European-Non Finnish (NFE) AF: 9.41e-7 AC: 1 AN: 1063260

Other (OTH) AF: 0.00 AC: 0 AN: 56334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.025
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
PromoterAI		0.010	Neutral
Varity_R		0.083
gMVP		0.29
Mutation Taster		=96/4	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

hg19: chr2-238768337;