chr2-237911760-A-G

Position:

• chr2-237911760-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005855.4(RAMP1):​c.424A>G​(p.Lys142Glu) 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 pathogenic 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: 3.07

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAMP1	NM_005855.4	c.424A>G	p.Lys142Glu	missense_variant	3/3	ENST00000254661.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAMP1	ENST00000254661.5	c.424A>G	p.Lys142Glu	missense_variant	3/3	1	NM_005855.4	P1
RAMP1	ENST00000403885.1	c.358A>G	p.Lys120Glu	missense_variant	3/3	3
RAMP1	ENST00000404910.6	c.358A>G	p.Lys120Glu	missense_variant	3/3	2
RAMP1	ENST00000409726.5	c.358A>G	p.Lys120Glu	missense_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Sep 27, 2021

The c.424A>G (p.K142E) alteration is located in exon 3 (coding exon 3) of the RAMP1 gene. This alteration results from a A to G substitution at nucleotide position 424, causing the lysine (K) at amino acid position 142 to be replaced by a glutamic acid (E). 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	0.30
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;D;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	.;D;.;D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.1	.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.99	.;D;.;.
Vest4		0.58
MutPred		0.68		.;Loss of methylation at K142 (P = 0.007);.;.;
MVP		0.80
MPC		0.062
ClinPred		0.97	D
GERP RS		2.5
Varity_R		0.89
gMVP		0.88

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: chr2-238820402;