11-68903951-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002180.3(IGHMBP2):c.-2C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,569,878 control chromosomes in the GnomAD database, including 41,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 3026 hom., cov: 35)

Exomes 𝑓: 0.23 ( 38756 hom. )

Consequence

IGHMBP2
NM_002180.3 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0100

Publications

15 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 links:

MRPL21 (HGNC:14479): (mitochondrial ribosomal protein L21) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. Multiple transcript variants encoding different isoforms were identified through sequence analysis although some may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Jul 2008]

MRPL21 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=-0.53).

BP6

Variant 11-68903951-C-T is Benign according to our data. Variant chr11-68903951-C-T is described in ClinVar as [Benign]. Clinvar id is 258555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 link	c.-2C>T		5_prime_UTR_variant	Exon 1 of 15	ENST00000255078.8	NP_002171.2	P38935
MRPL21	NM_181514.2 link	c.-141G>A		upstream_gene_variant		ENST00000362034.7	NP_852615.1	Q7Z2W9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 link	c.-2C>T		5_prime_UTR_variant	Exon 1 of 15	1	NM_002180.3	ENSP00000255078.4		P38935
MRPL21	ENST00000362034.7 link	c.-141G>A		upstream_gene_variant		1	NM_181514.2	ENSP00000354580.2		Q7Z2W9-1

Frequencies

GnomAD3 genomes

AF:

0.184

AC:

27968

AN:

152008

Hom.:

3023

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.305

Gnomad AMR

AF:

0.208

Gnomad ASJ

AF:

0.287

Gnomad EAS

AF:

0.0241

Gnomad SAS

AF:

0.0607

Gnomad FIN

AF:

0.124

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.250

Gnomad OTH

AF:

0.244

GnomAD2 exomes

AF:

0.187

AC:

33258

AN:

177460

AF XY:

0.186

show subpopulations

Gnomad AFR exome

AF:

0.106

Gnomad AMR exome

AF:

0.191

Gnomad ASJ exome

AF:

0.284

Gnomad EAS exome

AF:

0.0257

Gnomad FIN exome

AF:

0.132

Gnomad NFE exome

AF:

0.265

Gnomad OTH exome

AF:

0.225

GnomAD4 exome

AF:

0.225

AC:

319618

AN:

1417752

Hom.:

38756

Cov.:

AF XY:

0.221

AC XY:

155113

AN XY:

701912

show subpopulations

African (AFR)

AF:

0.100

AC:

3243

AN:

32322

American (AMR)

AF:

0.188

AC:

7055

AN:

37454

Ashkenazi Jewish (ASJ)

AF:

0.283

AC:

7194

AN:

25396

East Asian (EAS)

AF:

0.0273

AC:

1013

AN:

37130

South Asian (SAS)

AF:

0.0706

AC:

5817

AN:

82378

European-Finnish (FIN)

AF:

0.133

AC:

6564

AN:

49290

Middle Eastern (MID)

AF:

0.217

AC:

1239

AN:

5700

European-Non Finnish (NFE)

AF:

0.252

AC:

274957

AN:

1089384

Other (OTH)

AF:

0.214

AC:

12536

AN:

58698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

12374

24748

37123

49497

61871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.184

AC:

27984

AN:

152126

Hom.:

3026

Cov.:

AF XY:

0.176

AC XY:

13124

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.103

AC:

4282

AN:

41508

American (AMR)

AF:

0.207

AC:

3174

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.287

AC:

995

AN:

3470

East Asian (EAS)

AF:

0.0244

AC:

125

AN:

5132

South Asian (SAS)

AF:

0.0601

AC:

290

AN:

4824

European-Finnish (FIN)

AF:

0.124

AC:

1315

AN:

10610

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.250

AC:

16957

AN:

67956

Other (OTH)

AF:

0.241

AC:

509

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1090

2181

3271

4362

5452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.237

Hom.:

3094

Bravo

AF:

0.190

Asia WGS

AF:

0.0550

AC:

192

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 29, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 25% of total chromosomes in ExAC -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 16, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive distal spinal muscular atrophy 1

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2S

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

PhyloP100

0.010

PromoterAI

0.0082

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Mutation Taster

=300/0

polymorphism (auto)

(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

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11-68903951-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over