22-50482891-C-A

Variant names:

• chr22-50482891-C-A
• rs555246517
• NM_001253845.2:c.435C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001253845.2(ADM2):​c.435C>A​(p.His145Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ADM2 NM_001253845.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38449734).

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.435C>A	p.His145Gln	missense	Exon 3 of 3	NP_001240774.1	Q7Z4H4
	ADM2	NM_001369882.1		c.435C>A	p.His145Gln	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.435C>A	p.His145Gln	missense	Exon 3 of 3	ENSP00000379086.1	Q7Z4H4
	ADM2	ENST00000395738.2	TSL:1	c.435C>A	p.His145Gln	missense	Exon 2 of 2	ENSP00000379087.2	Q7Z4H4
	SBF1	ENST00000685180.1		n.131+902G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445430 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718542

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 43542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39226

South Asian (SAS) AF: 0.00 AC: 0 AN: 84874

European-Finnish (FIN) AF: 0.0000224 AC: 1 AN: 44544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108364

Other (OTH) AF: 0.00 AC: 0 AN: 59884

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.24		Gain of solvent accessibility (P = 0.0044)
MVP		0.088
MPC		0.28
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.66
gMVP		0.28
Mutation Taster		=41/59	disease causing

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: rs555246517; hg19: chr22-50921320;