Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002180.3(IGHMBP2):c.*22C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,587,190 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 14 hom., cov: 33)

Exomes 𝑓: 0.00070 ( 12 hom. )

Consequence

IGHMBP2
NM_002180.3 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.558

Publications

0 publications found

Variant links:

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

IGHMBP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 11-68939753-C-T is Benign according to our data. Variant chr11-68939753-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258554.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 = 0.00737 (1122/152298) while in subpopulation AFR AF = 0.0262 (1087/41564). AF 95% confidence interval is 0.0249. There are 14 homozygotes in GnomAd4. There are 525 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	NM_002180.3	MANE Select	c.*22C>T		3_prime_UTR	Exon 15 of 15	NP_002171.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.*22C>T	3_prime_UTR	Exon 15 of 15	ENSP00000255078.4
IGHMBP2	ENST00000544521.1	TSL:1	n.835C>T	non_coding_transcript_exon	Exon 2 of 2
IGHMBP2	ENST00000925063.1		c.*22C>T	3_prime_UTR	Exon 14 of 14	ENSP00000595122.1

Frequencies

GnomAD3 genomes

AF:

0.00734

AC:

1117

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0261

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00207

AC:

415

AN:

200920

AF XY:

0.00154

show subpopulations

Gnomad AFR exome

AF:

0.0297

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000684

Gnomad OTH exome

AF:

0.000782

GnomAD4 exome

AF:

0.000696

AC:

999

AN:

1434892

Hom.:

Cov.:

AF XY:

0.000619

AC XY:

440

AN XY:

711356

show subpopulations

African (AFR)

AF:

0.0246

AC:

817

AN:

33274

American (AMR)

AF:

0.00154

AC:

AN:

39616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25444

East Asian (EAS)

AF:

0.00

AC:

AN:

38866

South Asian (SAS)

AF:

0.0000605

AC:

AN:

82676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50814

Middle Eastern (MID)

AF:

0.000947

AC:

AN:

5282

European-Non Finnish (NFE)

AF:

0.0000164

AC:

AN:

1099492

Other (OTH)

AF:

0.00156

AC:

AN:

59428

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

121

182

242

303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00737

AC:

1122

AN:

152298

Hom.:

Cov.:

AF XY:

0.00705

AC XY:

525

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0262

AC:

1087

AN:

41564

American (AMR)

AF:

0.00170

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68018

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

120

180

240

300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00373

Hom.:

Bravo

AF:

0.00846

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive distal spinal muscular atrophy 1 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.7

(source)

DANN

Benign

0.67

PhyloP100

0.56

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over