22-50482700-C-G

Variant names:

• chr22-50482700-C-G
• rs183410750
• NM_001253845.2:c.244C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001253845.2(ADM2):​c.244C>G​(p.Leu82Val) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L82F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADM2 NM_001253845.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.547
• Publications: 0 publications found

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]

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 4B3

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06391388).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001253845.2. 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
	ADM2	NM_001253845.2	MANE Select	c.244C>G	p.Leu82Val	missense	Exon 3 of 3	NP_001240774.1	Q7Z4H4
	ADM2	NM_001369882.1		c.244C>G	p.Leu82Val	missense	Exon 2 of 2	NP_001356811.1	Q7Z4H4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADM2	ENST00000395737.2	TSL:1 MANE Select	c.244C>G	p.Leu82Val	missense	Exon 3 of 3	ENSP00000379086.1	Q7Z4H4
	ADM2	ENST00000395738.2	TSL:1	c.244C>G	p.Leu82Val	missense	Exon 2 of 2	ENSP00000379087.2	Q7Z4H4
	SBF1	ENST00000685180.1		n.131+1093G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.55
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.058
Sift	Benign	0.28	T
Sift4G	Benign	0.62	T
Polyphen		0.15	B
Vest4		0.017
MutPred		0.22		Gain of sheet (P = 0.0827)
MVP		0.030
MPC		0.12
ClinPred		0.17	T
GERP RS		3.6
Varity_R		0.078
gMVP		0.061
Mutation Taster		=98/2	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

dbSNP: rs183410750; hg19: chr22-50921129;