Genetic Variant RAMP2:p.Ala9Thr (chr17-42761286-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005854.3(RAMP2):c.25G>A(p.Ala9Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,385,074 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: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

RAMP2
NM_005854.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.340

Publications

1 publications found

Variant links:

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 links:

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

RAMP2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02159369).

BS2

High AC in GnomAd4 at 48 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005854.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAMP2	NM_005854.3	MANE Select	c.25G>A	p.Ala9Thr	missense	Exon 1 of 4	NP_005845.2	O60895-1
RAMP2-AS1	NR_024461.1		n.-29C>T		upstream_gene	N/A
RAMP2-AS1	NR_024462.1		n.-29C>T		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAMP2	ENST00000253796.10	TSL:1 MANE Select	c.25G>A	p.Ala9Thr	missense	Exon 1 of 4	ENSP00000253796.3	O60895-1
RAMP2	ENST00000587142.5	TSL:1	c.25G>A	p.Ala9Thr	missense	Exon 1 of 4	ENSP00000466455.1	O60895-2
RAMP2	ENST00000904024.1		c.25G>A	p.Ala9Thr	missense	Exon 1 of 4	ENSP00000574083.1

Frequencies

GnomAD3 genomes

AF:

0.000316

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000676

AC:

AN:

44396

AF XY:

0.0000760

show subpopulations

Gnomad AFR exome

AF:

0.00342

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000195

AC:

AN:

1232920

Hom.:

Cov.:

AF XY:

0.0000149

AC XY:

AN XY:

603134

show subpopulations

African (AFR)

AF:

0.000766

AC:

AN:

24796

American (AMR)

AF:

0.00

AC:

AN:

17744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19508

East Asian (EAS)

AF:

0.00

AC:

AN:

26856

South Asian (SAS)

AF:

0.0000176

AC:

AN:

56932

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28920

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3560

European-Non Finnish (NFE)

AF:

0.00000199

AC:

AN:

1004144

Other (OTH)

AF:

0.0000396

AC:

AN:

50460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000315

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

41546

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000321

ExAC

AF:

0.0000242

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.45

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.022

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PhyloP100

0.34

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.13

REVEL

Benign

0.073

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.10

MutPred

0.30

Gain of relative solvent accessibility (P = 0.0082)

MVP

0.68

MPC

0.19

ClinPred

0.076

GERP RS

2.5

PromoterAI

-0.10

Neutral

(source)

Varity_R

0.094

gMVP

0.27

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over