rs140654955

Variant names:

• chr11-68933353-C-T
• rs140654955
• NM_002180.3:c.1290C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_002180.3(IGHMBP2):​c.1290C>T​(p.Tyr430Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000898 in 1,613,076 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00093 (1 hom.)
• Consequence: IGHMBP2 NM_002180.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -2.51
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 11-68933353-C-T is Benign according to our data. Variant chr11-68933353-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 305844.
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000597 (91/152306) while in subpopulation NFE AF = 0.00104 (71/68024). AF 95% confidence interval is 0.000848. There are 1 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.1290C>T	p.Tyr430Tyr	synonymous	Exon 9 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.1290C>T	p.Tyr430Tyr	synonymous	Exon 9 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000675615.1		c.1290C>T	p.Tyr430Tyr	synonymous	Exon 9 of 14	ENSP00000502413.1	A0A6Q8PGT6
	IGHMBP2	ENST00000925063.1		c.1236-442C>T		intron	N/A	ENSP00000595122.1

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152188 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000642 AC: 159 AN: 247794 AF XY: 0.000699

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000930 AC: 1358 AN: 1460770 Hom.: 1 Cov.: 32 AF XY: 0.000914 AC XY: 664 AN XY: 726622

African (AFR) AF: 0.000269 AC: 9 AN: 33476

American (AMR) AF: 0.000246 AC: 11 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.000500 AC: 43 AN: 86040

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52822

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00112 AC: 1249 AN: 1111848

Other (OTH) AF: 0.000696 AC: 42 AN: 60368

GnomAD4 genome AF: 0.000597 AC: 91 AN: 152306 Hom.: 1 Cov.: 33 AF XY: 0.000577 AC XY: 43 AN XY: 74482

African (AFR) AF: 0.000337 AC: 14 AN: 41570

American (AMR) AF: 0.000131 AC: 2 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00104 AC: 71 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000899 Hom.: 0

Bravo AF: 0.000593

EpiCase AF: 0.000981

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	1	-	Autosomal recessive distal spinal muscular atrophy 1 (1)
-	-	1	Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.12
DANN	Benign	0.33
PhyloP100		-2.5
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: rs140654955; hg19: chr11-68700821;