11-68932956-C-T

Variant names:

• chr11-68932956-C-T
• rs478647
• NM_002180.3:c.1236-343C>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.1236-343C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 377,982 control chromosomes in the GnomAD database, including 17,136 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 0.25 (5428 hom., cov: 32)
  • Exomes 𝑓: 0.31 (11708 hom.)
• Consequence: IGHMBP2 NM_002180.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.818
• Publications: 21 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

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.1236-343C>T		intron	N/A	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.1236-343C>T		intron	N/A	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000925063.1		c.1236-839C>T		intron	N/A	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.1236-343C>T		intron	N/A	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37876 AN: 151828 Hom.: 5433 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.239

GnomAD4 exome AF: 0.308 AC: 69593 AN: 226038 Hom.: 11708 Cov.: 0 AF XY: 0.320 AC XY: 37849 AN XY: 118098

African (AFR) AF: 0.125 AC: 933 AN: 7470

American (AMR) AF: 0.148 AC: 1645 AN: 11124

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 2491 AN: 6872

East Asian (EAS) AF: 0.206 AC: 2706 AN: 13162

South Asian (SAS) AF: 0.446 AC: 13421 AN: 30098

European-Finnish (FIN) AF: 0.364 AC: 4261 AN: 11692

Middle Eastern (MID) AF: 0.351 AC: 329 AN: 936

European-Non Finnish (NFE) AF: 0.303 AC: 40017 AN: 131910

Other (OTH) AF: 0.297 AC: 3790 AN: 12774

GnomAD4 genome AF: 0.249 AC: 37869 AN: 151944 Hom.: 5428 Cov.: 32 AF XY: 0.254 AC XY: 18883 AN XY: 74240

African (AFR) AF: 0.128 AC: 5327 AN: 41486

American (AMR) AF: 0.180 AC: 2753 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1307 AN: 3468

East Asian (EAS) AF: 0.201 AC: 1033 AN: 5134

South Asian (SAS) AF: 0.454 AC: 2176 AN: 4790

European-Finnish (FIN) AF: 0.365 AC: 3850 AN: 10558

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.304 AC: 20676 AN: 67920

Other (OTH) AF: 0.237 AC: 501 AN: 2110

Alfa AF: 0.286 Hom.: 4886

Bravo AF: 0.225

Asia WGS AF: 0.304 AC: 1054 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.095
DANN	Benign	0.43
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs478647; hg19: chr11-68700424;