11-68932891-C-T

Variant names:

• chr11-68932891-C-T
• rs655915
• NM_002180.3:c.1236-408C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002180.3(IGHMBP2):​c.1236-408C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 231,170 control chromosomes in the GnomAD database, including 69,293 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.76 (44629 hom., cov: 30)
  • Exomes 𝑓: 0.78 (24664 hom.)
• Consequence: IGHMBP2 NM_002180.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.28
• 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: 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3	c.1236-408C>T		intron_variant	Intron 8 of 14	ENST00000255078.8	NP_002171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.1236-408C>T		intron_variant	Intron 8 of 14	1	NM_002180.3	ENSP00000255078.4

Frequencies

GnomAD3 genomes AF: 0.758 AC: 115071 AN: 151886 Hom.: 44599 Cov.: 30

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.912

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.796

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.842

Gnomad OTH AF: 0.786

GnomAD4 exome AF: 0.781 AC: 61836 AN: 79166 Hom.: 24664 Cov.: 0 AF XY: 0.780 AC XY: 32054 AN XY: 41118

African (AFR) AF: 0.611 AC: 2089 AN: 3418

American (AMR) AF: 0.795 AC: 3693 AN: 4646

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 1669 AN: 2060

East Asian (EAS) AF: 0.461 AC: 2141 AN: 4644

South Asian (SAS) AF: 0.732 AC: 7220 AN: 9864

European-Finnish (FIN) AF: 0.750 AC: 2470 AN: 3294

Middle Eastern (MID) AF: 0.819 AC: 254 AN: 310

European-Non Finnish (NFE) AF: 0.836 AC: 39057 AN: 46722

Other (OTH) AF: 0.771 AC: 3243 AN: 4208

GnomAD4 genome AF: 0.758 AC: 115152 AN: 152004 Hom.: 44629 Cov.: 30 AF XY: 0.757 AC XY: 56200 AN XY: 74284

African (AFR) AF: 0.623 AC: 25817 AN: 41430

American (AMR) AF: 0.826 AC: 12630 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 2762 AN: 3472

East Asian (EAS) AF: 0.485 AC: 2494 AN: 5144

South Asian (SAS) AF: 0.728 AC: 3488 AN: 4794

European-Finnish (FIN) AF: 0.757 AC: 8008 AN: 10580

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.842 AC: 57236 AN: 67976

Other (OTH) AF: 0.783 AC: 1654 AN: 2112

Alfa AF: 0.816 Hom.: 28931

Bravo AF: 0.757

Asia WGS AF: 0.620 AC: 2158 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.14
DANN	Benign	0.55
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs655915; hg19: chr11-68700359;