Variant 22-50482725-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001253845.2(ADM2):c.269C>T(p.Ser90Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000336 in 1,281,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000050 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

ADM2
NM_001253845.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.366

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:):

SBF1 links:

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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=0.05608806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADM2	NM_001253845.2 linkuse as main transcript	c.269C>T	p.Ser90Leu	missense_variant	3/3	ENST00000395737.2	NP_001240774.1	Q7Z4H4
ADM2	NM_001369882.1 linkuse as main transcript	c.269C>T	p.Ser90Leu	missense_variant	2/2		NP_001356811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADM2	ENST00000395737.2 linkuse as main transcript	c.269C>T	p.Ser90Leu	missense_variant	3/3	1	NM_001253845.2	ENSP00000379086.1	Q7Z4H4
ADM2	ENST00000395738.2 linkuse as main transcript	c.269C>T	p.Ser90Leu	missense_variant	2/2	1		ENSP00000379087.2	Q7Z4H4
SBF1	ENST00000685180.1 linkuse as main transcript	n.131+1068G>A		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0000501

AC:

AN:

119770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000601

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000174

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:

0.0000371

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000653

AC:

AN:

229810

Hom.:

AF XY:

0.0000787

AC XY:

AN XY:

127080

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000180

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000576

Gnomad SAS exome

AF:

0.000101

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000394

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.0000319

AC:

AN:

1161392

Hom.:

Cov.:

AF XY:

0.0000345

AC XY:

AN XY:

579494

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000204

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000840

Gnomad4 SAS exome

AF:

0.0000762

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000236

Gnomad4 OTH exome

AF:

0.0000415

GnomAD4 genome

AF:

0.0000501

AC:

AN:

119770

Hom.:

Cov.:

AF XY:

0.0000514

AC XY:

AN XY:

58332

show subpopulations

Gnomad4 AFR

AF:

0.0000601

Gnomad4 AMR

AF:

0.000174

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000371

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000735

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000522

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2022

The c.269C>T (p.S90L) 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 269, causing the serine (S) at amino acid position 90 to be replaced by a leucine (L). 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

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.8

DANN

Benign

0.94

DEOGEN2

Benign

0.0072

T;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.48

.;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.85

L;L

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.053

Sift

Benign

0.11

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.79

P;P

Vest4

0.077

MutPred

0.29

Loss of phosphorylation at S90 (P = 0.0061);Loss of phosphorylation at S90 (P = 0.0061);

MVP

0.030

MPC

0.21

ClinPred

0.045

GERP RS

1.0

Varity_R

0.040

gMVP

0.15

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