11-68933357-G-A

Variant names:

• chr11-68933357-G-A
• rs116012780
• NM_002180.3:c.1294G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002180.3(IGHMBP2):​c.1294G>A​(p.Ala432Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000755 in 1,613,182 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A432V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (5 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.37
• Publications: 1 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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_002180.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.004066944).
• BP6: Variant 11-68933357-G-A is Benign according to our data. Variant chr11-68933357-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 386157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00408 (622/152326) while in subpopulation AFR AF = 0.0143 (594/41570). AF 95% confidence interval is 0.0133. There are 3 homozygotes in GnomAd4. There are 288 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1294G>A	p.Ala432Thr	missense	Exon 9 of 15	NP_002171.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.1294G>A	p.Ala432Thr	missense	Exon 9 of 15	ENSP00000255078.4
	IGHMBP2	ENST00000675615.1		c.1294G>A	p.Ala432Thr	missense	Exon 9 of 14	ENSP00000502413.1
	IGHMBP2	ENST00000925063.1		c.1236-438G>A		intron	N/A	ENSP00000595122.1

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 623 AN: 152208 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00103 AC: 256 AN: 248084 AF XY: 0.000765

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.000524

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000408 AC: 596 AN: 1460856 Hom.: 5 Cov.: 32 AF XY: 0.000336 AC XY: 244 AN XY: 726694

African (AFR) AF: 0.0145 AC: 484 AN: 33478

American (AMR) AF: 0.000448 AC: 20 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000395 AC: 34 AN: 86048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111898

Other (OTH) AF: 0.000745 AC: 45 AN: 60378

GnomAD4 genome AF: 0.00408 AC: 622 AN: 152326 Hom.: 3 Cov.: 33 AF XY: 0.00387 AC XY: 288 AN XY: 74486

African (AFR) AF: 0.0143 AC: 594 AN: 41570

American (AMR) AF: 0.00131 AC: 20 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

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

Alfa AF: 0.000732 Hom.: 1

Bravo AF: 0.00454

ESP6500AA AF: 0.0168 AC: 74

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00140 AC: 170

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.96	L
PhyloP100		2.4
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.14
Sift	Benign	0.32	T
Sift4G	Benign	0.52	T
Polyphen		0.012	B
Vest4		0.098
MVP		0.81
MPC		0.21
ClinPred		0.011	T
GERP RS		3.0
Varity_R		0.095
gMVP		0.26
Mutation Taster		=97/3	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: rs116012780; hg19: chr11-68700825;