11-68906133-C-T

Variant names:

• chr11-68906133-C-T
• rs117061430
• NM_002180.3:c.151C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP3

The NM_002180.3(IGHMBP2):​c.151C>T​(p.Gln51*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGHMBP2 NM_002180.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.85
• Publications: 9 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: Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary peripheral neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	NM_002180.3	MANE Select	c.151C>T	p.Gln51*	stop_gained	Exon 2 of 15	NP_002171.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.151C>T	p.Gln51*	stop_gained	Exon 2 of 15	ENSP00000255078.4
	IGHMBP2	ENST00000675615.1		c.151C>T	p.Gln51*	stop_gained	Exon 2 of 14	ENSP00000502413.1
	IGHMBP2	ENST00000539224.2	TSL:3	n.112C>T		non_coding_transcript_exon	Exon 2 of 8	ENSP00000440465.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251490 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		3.9
Vest4		0.87
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.57		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs117061430; hg19: chr11-68673601;