NM_002180.3:c.1418+18A>G

Variant names:

• chr11-68933499-A-G
• rs112575423
• NM_002180.3:c.1418+18A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002180.3(IGHMBP2):​c.1418+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,603,258 control chromosomes in the GnomAD database, including 1,603 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (736 hom., cov: 33)
  • Exomes 𝑓: 0.015 (867 hom.)
• Consequence: IGHMBP2 NM_002180.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.04
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 11-68933499-A-G is Benign according to our data. Variant chr11-68933499-A-G is described in ClinVar as Benign. ClinVar VariationId is 258556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 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.1418+18A>G		intron	N/A	NP_002171.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.1418+18A>G		intron	N/A	ENSP00000255078.4
	IGHMBP2	ENST00000925063.1		c.1236-296A>G		intron	N/A	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.1418+18A>G		intron	N/A	ENSP00000502413.1

Frequencies

GnomAD3 genomes AF: 0.0595 AC: 9037 AN: 151986 Hom.: 725 Cov.: 33

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0318

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.0278

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00841

Gnomad OTH AF: 0.0566

GnomAD2 exomes AF: 0.0227 AC: 5212 AN: 229142 AF XY: 0.0210

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.00517

Gnomad FIN exome AF: 0.00309

Gnomad NFE exome AF: 0.00857

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0146 AC: 21163 AN: 1451154 Hom.: 867 Cov.: 32 AF XY: 0.0145 AC XY: 10431 AN XY: 721046

African (AFR) AF: 0.196 AC: 6516 AN: 33290

American (AMR) AF: 0.0181 AC: 790 AN: 43538

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 475 AN: 25864

East Asian (EAS) AF: 0.0284 AC: 1117 AN: 39310

South Asian (SAS) AF: 0.0267 AC: 2260 AN: 84668

European-Finnish (FIN) AF: 0.00280 AC: 144 AN: 51472

Middle Eastern (MID) AF: 0.0391 AC: 225 AN: 5750

European-Non Finnish (NFE) AF: 0.00738 AC: 8176 AN: 1107292

Other (OTH) AF: 0.0243 AC: 1460 AN: 59970

GnomAD4 genome AF: 0.0597 AC: 9085 AN: 152104 Hom.: 736 Cov.: 33 AF XY: 0.0587 AC XY: 4362 AN XY: 74356

African (AFR) AF: 0.184 AC: 7626 AN: 41468

American (AMR) AF: 0.0317 AC: 484 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3470

East Asian (EAS) AF: 0.0116 AC: 60 AN: 5170

South Asian (SAS) AF: 0.0278 AC: 134 AN: 4812

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10596

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00844 AC: 574 AN: 67990

Other (OTH) AF: 0.0598 AC: 126 AN: 2108

Alfa AF: 0.0319 Hom.: 512

Bravo AF: 0.0661

Asia WGS AF: 0.0470 AC: 164 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.18
DANN	Benign	0.27
PhyloP100		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs112575423; hg19: chr11-68700967;