11-68934480-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002180.3(IGHMBP2):c.1554C>T(p.Val518=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,608,376 control chromosomes in the GnomAD database, including 41,992 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3352 hom., cov: 33)
  • Exomes 𝑓: 0.22 (38640 hom.)
• Consequence: IGHMBP2 NM_002180.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.877

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 11-68934480-C-T is Benign according to our data. Variant chr11-68934480-C-T is described in ClinVar as [Benign]. Clinvar id is 258560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68934480-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.877 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGHMBP2	NM_002180.3	c.1554C>T	p.Val518=	synonymous_variant	11/15	ENST00000255078.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.1554C>T	p.Val518=	synonymous_variant	11/15	1	NM_002180.3	P1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30606 AN: 152126 Hom.: 3350 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.0300

Gnomad SAS AF: 0.0675

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.255

GnomAD3 exomes AF: 0.186 AC: 45258 AN: 243508 Hom.: 4805 AF XY: 0.185 AC XY: 24327 AN XY: 131736

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.184

Gnomad ASJ exome AF: 0.274

Gnomad EAS exome AF: 0.0291

Gnomad SAS exome AF: 0.0756

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.223 AC: 324909 AN: 1456132 Hom.: 38640 Cov.: 32 AF XY: 0.219 AC XY: 158478 AN XY: 723986

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.185

Gnomad4 ASJ exome AF: 0.277

Gnomad4 EAS exome AF: 0.0308

Gnomad4 SAS exome AF: 0.0779

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.201 AC: 30618 AN: 152244 Hom.: 3352 Cov.: 33 AF XY: 0.194 AC XY: 14425 AN XY: 74446

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.208

Gnomad4 ASJ AF: 0.280

Gnomad4 EAS AF: 0.0301

Gnomad4 SAS AF: 0.0669

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.246

Gnomad4 OTH AF: 0.252

Alfa AF: 0.234 Hom.: 2422

Bravo AF: 0.211

Asia WGS AF: 0.0700 AC: 248 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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: 23% of total chromosomes in ExAC -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive distal spinal muscular atrophy 1 Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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	-0.61
Cadd	Benign	3.8
Dann	Benign	0.90

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: rs11228413; hg19: chr11-68701948; COSMIC: COSV54824692; COSMIC: COSV54824692;