11-68903951-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0100

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr11-68903951-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
IGHMBP2	NM_002180.3	c.-2C>T		5_prime_UTR_variant	1/15	ENST00000255078.8
IGHMBP2	XM_005273976.3	c.-2C>T		5_prime_UTR_variant	1/9
IGHMBP2	XM_017017671.3	c.-2C>T		5_prime_UTR_variant	1/12
IGHMBP2	XM_047426881.1	c.-2C>T		5_prime_UTR_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.-2C>T		5_prime_UTR_variant	1/15	1	NM_002180.3	P1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27968 AN: 152008 Hom.: 3023 Cov.: 35

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

GnomAD3 exomes AF: 0.187 AC: 33258 AN: 177460 Hom.: 3698 AF XY: 0.186 AC XY: 17875 AN XY: 96106

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 SAS exome AF: 0.0713

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.: 40 AF XY: 0.221 AC XY: 155113 AN XY: 701912

Gnomad4 AFR exome AF: 0.100

Gnomad4 AMR exome AF: 0.188

Gnomad4 ASJ exome AF: 0.283

Gnomad4 EAS exome AF: 0.0273

Gnomad4 SAS exome AF: 0.0706

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.214

GnomAD4 genome AF: 0.184 AC: 27984 AN: 152126 Hom.: 3026 Cov.: 35 AF XY: 0.176 AC XY: 13124 AN XY: 74374

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.287

Gnomad4 EAS AF: 0.0244

Gnomad4 SAS AF: 0.0601

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.250

Gnomad4 OTH AF: 0.241

Alfa AF: 0.240 Hom.: 2515

Bravo AF: 0.190

Asia WGS AF: 0.0550 AC: 192 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2016	- -

Autosomal recessive distal spinal muscular atrophy 1 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2017	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease axonal type 2S Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	15
Dann	Uncertain	0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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

LitVar

Other links and lift over

dbSNP: rs4930624; hg19: chr11-68671419;