rs34617762

Positions:

• chr11-68906162-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002180.3(IGHMBP2):​c.180C>T​(p.Tyr60Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,126 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (17 hom., cov: 32)
  • Exomes 𝑓: 0.011 (124 hom.)
• Consequence: IGHMBP2 NM_002180.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.67

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 11-68906162-C-T is Benign according to our data. Variant chr11-68906162-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68906162-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00944 (1437/152282) while in subpopulation NFE AF= 0.0127 (867/68024). AF 95% confidence interval is 0.012. There are 17 homozygotes in gnomad4. There are 750 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3	c.180C>T	p.Tyr60Tyr	synonymous_variant	2/15	ENST00000255078.8	NP_002171.2
IGHMBP2	XM_047426881.1	c.180C>T	p.Tyr60Tyr	synonymous_variant	2/15		XP_047282837.1
IGHMBP2	XM_017017671.3	c.180C>T	p.Tyr60Tyr	synonymous_variant	2/12		XP_016873160.1
IGHMBP2	XM_005273976.3	c.180C>T	p.Tyr60Tyr	synonymous_variant	2/9		XP_005274033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.180C>T	p.Tyr60Tyr	synonymous_variant	2/15	1	NM_002180.3	ENSP00000255078.4

Frequencies

GnomAD3 genomes AF: 0.00944 AC: 1437 AN: 152164 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00950 AC: 2390 AN: 251482 Hom.: 20 AF XY: 0.0104 AC XY: 1417 AN XY: 135920

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00653

Gnomad ASJ exome AF: 0.00734

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00310

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0113 AC: 16575 AN: 1461844 Hom.: 124 Cov.: 31 AF XY: 0.0114 AC XY: 8298 AN XY: 727228

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.00722

Gnomad4 ASJ exome AF: 0.00781

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00329

Gnomad4 FIN exome AF: 0.0176

Gnomad4 NFE exome AF: 0.0126

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.00944 AC: 1437 AN: 152282 Hom.: 17 Cov.: 32 AF XY: 0.0101 AC XY: 750 AN XY: 74456

Gnomad4 AFR AF: 0.00258

Gnomad4 AMR AF: 0.00987

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0209

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0107 Hom.: 5

Bravo AF: 0.00864

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0170

EpiControl AF: 0.0174

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	IGHMBP2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -

not specified Benign:3

Likely 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: 2.1% of Finnish chromosomes in ExAC -
Benign, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Autosomal recessive distal spinal muscular atrophy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.4
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34617762; hg19: chr11-68673630;