22-50482700-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001253845.2(ADM2):c.244C>T(p.Leu82Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000735 in 1,605,722 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 1 hom. )

Consequence

ADM2
NM_001253845.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.547

Variant links:

Genes affected

ADM2 (HGNC:28898): (adrenomedullin 2) This gene encodes a member of the calcitonin gene-related peptide (CGRP)/calcitonin family of hormones that play a role in the regulation of cardiovascular homeostasis, prolactin release, anti-diuresis, anti-natriuresis, and regulation of food and water intake. The encoded protein is proteolytically processed to generate one or more biologically active peptides. [provided by RefSeq, Jul 2015]

ADM2 links:

SBF1 (HGNC:10542): (SET binding factor 1) This gene encodes a member of the protein-tyrosine phosphatase family. However, the encoded protein does not appear to be a catalytically active phosphatase because it lacks several amino acids in the catalytic pocket. This protein contains a Guanine nucleotide exchange factor (GEF) domain which is necessary for its role in growth and differentiation. Mutations in this gene have been associated with Charcot-Marie-Tooth disease 4B3. Pseudogenes of this gene have been defined on chromosomes 1 and 8. [provided by RefSeq, Dec 2014]

SBF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009290159).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADM2	NM_001253845.2 link	c.244C>T	p.Leu82Phe	missense_variant	Exon 3 of 3	ENST00000395737.2	NP_001240774.1	Q7Z4H4
ADM2	NM_001369882.1 link	c.244C>T	p.Leu82Phe	missense_variant	Exon 2 of 2		NP_001356811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADM2	ENST00000395737.2 link	c.244C>T	p.Leu82Phe	missense_variant	Exon 3 of 3	1	NM_001253845.2	ENSP00000379086.1	Q7Z4H4
ADM2	ENST00000395738.2 link	c.244C>T	p.Leu82Phe	missense_variant	Exon 2 of 2	1		ENSP00000379087.2	Q7Z4H4
SBF1	ENST00000685180.1 link	n.131+1093G>A		intron_variant	Intron 1 of 8

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000984

AC:

AN:

233652

Hom.:

AF XY:

0.0000853

AC XY:

AN XY:

128972

show subpopulations

Gnomad AFR exome

AF:

0.00131

Gnomad AMR exome

AF:

0.0000889

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000193

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000447

AC:

AN:

1453358

Hom.:

Cov.:

AF XY:

0.0000443

AC XY:

AN XY:

722138

show subpopulations

Gnomad4 AFR exome

AF:

0.00135

Gnomad4 AMR exome

AF:

0.000158

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000668

GnomAD4 genome

AF:

0.000348

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000155

Hom.:

Bravo

AF:

0.000363

ExAC

AF:

0.000142

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.244C>T (p.L82F) alteration is located in exon 2 (coding exon 2) of the ADM2 gene. This alteration results from a C to T substitution at nucleotide position 244, causing the leucine (L) at amino acid position 82 to be replaced by a phenylalanine (F). 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

0.10

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0076

T;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.44

.;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.0093

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.054

Sift

Benign

0.11

T;T

Sift4G

Benign

0.74

T;T

Polyphen

0.29

B;B

Vest4

0.023

MVP

0.030

MPC

0.31

ClinPred

0.024

GERP RS

3.6

Varity_R

0.098

gMVP

0.069

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over