11-68929226-C-T

Variant names:

• chr11-68929226-C-T
• rs148157556
• NM_002180.3:c.1104C>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.1104C>T​(p.Tyr368Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00661 in 1,613,790 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (74 hom.)
• Consequence: IGHMBP2 NM_002180.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.44

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=-0.49).
• BP6: Variant 11-68929226-C-T is Benign according to our data. Variant chr11-68929226-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 198778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68929226-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00546 (832/152304) while in subpopulation AMR AF= 0.00889 (136/15302). AF 95% confidence interval is 0.00767. There are 6 homozygotes in gnomad4. There are 407 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3	c.1104C>T	p.Tyr368Tyr	synonymous_variant	Exon 8 of 15	ENST00000255078.8	NP_002171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.1104C>T	p.Tyr368Tyr	synonymous_variant	Exon 8 of 15	1	NM_002180.3	ENSP00000255078.4

Frequencies

GnomAD3 genomes AF: 0.00541 AC: 823 AN: 152186 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.00328

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00714

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00678 AC: 1702 AN: 251104 Hom.: 17 AF XY: 0.00715 AC XY: 971 AN XY: 135772

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00705

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.00337

Gnomad SAS exome AF: 0.00660

Gnomad FIN exome AF: 0.00295

Gnomad NFE exome AF: 0.00763

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00672 AC: 9828 AN: 1461486 Hom.: 74 Cov.: 32 AF XY: 0.00681 AC XY: 4952 AN XY: 727086

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00689

Gnomad4 ASJ exome AF: 0.0182

Gnomad4 EAS exome AF: 0.00229

Gnomad4 SAS exome AF: 0.00679

Gnomad4 FIN exome AF: 0.00277

Gnomad4 NFE exome AF: 0.00679

Gnomad4 OTH exome AF: 0.00810

GnomAD4 genome AF: 0.00546 AC: 832 AN: 152304 Hom.: 6 Cov.: 32 AF XY: 0.00547 AC XY: 407 AN XY: 74468

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.0132

Gnomad4 EAS AF: 0.00328

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00717

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00687 Hom.: 4

Bravo AF: 0.00550

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.00900

EpiControl AF: 0.00966

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Aug 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IGHMBP2: BP4, BS2 -

Nov 08, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 14, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jul 11, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal recessive distal spinal muscular atrophy 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	2.4
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148157556; hg19: chr11-68696694;