rs1555247556

Variant names:

• chr11-68934488-A-G
• rs1555247556
• NM_002180.3:c.1562A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_002180.3(IGHMBP2):​c.1562A>G​(p.His521Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H521Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.93
• Publications: 0 publications found

Genes affected

IGHMBP2 (HGNC:5542): (immunoglobulin mu DNA binding protein 2) This gene encodes a helicase superfamily member that binds a specific DNA sequence from the immunoglobulin mu chain switch region. Mutations in this gene lead to spinal muscle atrophy with respiratory distress type 1. [provided by RefSeq, Jul 2008]

IGHMBP2 Gene-Disease associations (from GenCC):

• autosomal recessive distal spinal muscular atrophy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease axonal type 2S

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary peripheral neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_002180.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002180.3. 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
	IGHMBP2	NM_002180.3	MANE Select	c.1562A>G	p.His521Arg	missense	Exon 11 of 15	NP_002171.2	P38935

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.1562A>G	p.His521Arg	missense	Exon 11 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000541229.5	TSL:1	n.257A>G		non_coding_transcript_exon	Exon 2 of 4
	IGHMBP2	ENST00000925063.1		c.1379A>G	p.His460Arg	missense	Exon 10 of 14	ENSP00000595122.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459988 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726078

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 85708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111144

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.87
Sift	Benign	0.20	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.67		Gain of phosphorylation at S519 (P = 0.0795)
MVP		0.98
MPC		0.81
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.83
gMVP		0.90
Mutation Taster		=15/85	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: rs1555247556; hg19: chr11-68701956;