11-68906133-C-G

Variant names:

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

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.151C>G​(p.Gln51Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00594 in 1,614,180 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (41 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• 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: 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 (MetaRNN=0.0074187815).
• BP6: Variant 11-68906133-C-G is Benign according to our data. Variant chr11-68906133-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258557.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 = 0.00487 (741/152306) while in subpopulation NFE AF = 0.00691 (470/68022). AF 95% confidence interval is 0.00639. There are 6 homozygotes in GnomAd4. There are 389 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.151C>G	p.Gln51Glu	missense	Exon 2 of 15	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.151C>G	p.Gln51Glu	missense	Exon 2 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000925063.1		c.151C>G	p.Gln51Glu	missense	Exon 2 of 14	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.151C>G	p.Gln51Glu	missense	Exon 2 of 14	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes AF: 0.00488 AC: 742 AN: 152188 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00691

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00606 AC: 1525 AN: 251490 AF XY: 0.00604

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.00839

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00606 AC: 8853 AN: 1461874 Hom.: 41 Cov.: 31 AF XY: 0.00592 AC XY: 4305 AN XY: 727242

African (AFR) AF: 0.00114 AC: 38 AN: 33480

American (AMR) AF: 0.00148 AC: 66 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00248 AC: 214 AN: 86258

European-Finnish (FIN) AF: 0.0183 AC: 975 AN: 53418

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.00655 AC: 7281 AN: 1111998

Other (OTH) AF: 0.00439 AC: 265 AN: 60396

GnomAD4 genome AF: 0.00487 AC: 741 AN: 152306 Hom.: 6 Cov.: 32 AF XY: 0.00522 AC XY: 389 AN XY: 74478

African (AFR) AF: 0.00123 AC: 51 AN: 41568

American (AMR) AF: 0.00163 AC: 25 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.0161 AC: 171 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00691 AC: 470 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00562 Hom.: 3

Bravo AF: 0.00378

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00687 AC: 59

ExAC AF: 0.00628 AC: 762

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00557

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	0.081
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.20
Sift	Benign	0.97	T
Sift4G	Benign	0.92	T
Polyphen		0.0040	B
Vest4		0.45
MVP		0.83
MPC		0.21
ClinPred		0.015	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.51
Mutation Taster		=94/6	polymorphism

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: rs117061430; hg19: chr11-68673601; COSMIC: COSV54820857; COSMIC: COSV54820857;