11-68906247-G-A

Variant names:

• chr11-68906247-G-A
• rs118015540
• NM_002180.3:c.256+9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002180.3(IGHMBP2):​c.256+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,613,624 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (59 hom.)
• Consequence: IGHMBP2 NM_002180.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.797
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-68906247-G-A is Benign according to our data. Variant chr11-68906247-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00567 (863/152306) while in subpopulation NFE AF = 0.00938 (638/68026). AF 95% confidence interval is 0.00878. There are 4 homozygotes in GnomAd4. There are 386 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.256+9G>A		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.256+9G>A		intron	N/A	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000925063.1		c.256+9G>A		intron	N/A	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.256+9G>A		intron	N/A	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes AF: 0.00567 AC: 863 AN: 152188 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00938

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00508 AC: 1277 AN: 251290 AF XY: 0.00511

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.00836

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00795 AC: 11612 AN: 1461318 Hom.: 59 Cov.: 30 AF XY: 0.00777 AC XY: 5648 AN XY: 727022

African (AFR) AF: 0.00126 AC: 42 AN: 33462

American (AMR) AF: 0.00333 AC: 149 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26130

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39698

South Asian (SAS) AF: 0.000846 AC: 73 AN: 86242

European-Finnish (FIN) AF: 0.00511 AC: 273 AN: 53410

Middle Eastern (MID) AF: 0.00265 AC: 15 AN: 5652

European-Non Finnish (NFE) AF: 0.00960 AC: 10669 AN: 1111650

Other (OTH) AF: 0.00573 AC: 346 AN: 60358

GnomAD4 genome AF: 0.00567 AC: 863 AN: 152306 Hom.: 4 Cov.: 32 AF XY: 0.00518 AC XY: 386 AN XY: 74476

African (AFR) AF: 0.00176 AC: 73 AN: 41578

American (AMR) AF: 0.00543 AC: 83 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00500 AC: 53 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00938 AC: 638 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00844 Hom.: 7

Bravo AF: 0.00574

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal recessive distal spinal muscular atrophy 1 (2)
-	-	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	IGHMBP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.94
PhyloP100		-0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs118015540; hg19: chr11-68673715;