rs146217031

chr11-68908164-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_002180.3(IGHMBP2):c.276C>T(p.Tyr92=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: IGHMBP2 NM_002180.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0590

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 -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 11-68908164-C-T is Benign according to our data. Variant chr11-68908164-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 377972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.059 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00107 (163/152118) while in subpopulation AFR AF= 0.00359 (149/41490). AF 95% confidence interval is 0.00312. There are 0 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGHMBP2	NM_002180.3	c.276C>T	p.Tyr92=	synonymous_variant	3/15	ENST00000255078.8
IGHMBP2	XM_047426881.1	c.276C>T	p.Tyr92=	synonymous_variant	3/15
IGHMBP2	XM_017017671.3	c.276C>T	p.Tyr92=	synonymous_variant	3/12
IGHMBP2	XM_005273976.3	c.276C>T	p.Tyr92=	synonymous_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.276C>T	p.Tyr92=	synonymous_variant	3/15	1	NM_002180.3	P1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 159 AN: 152000 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00351

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000290 AC: 73 AN: 251354 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135858

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000109 AC: 159 AN: 1461802 Hom.: 0 Cov.: 32 AF XY: 0.0000839 AC XY: 61 AN XY: 727198

Gnomad4 AFR exome AF: 0.00326

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152118 Hom.: 0 Cov.: 31 AF XY: 0.00108 AC XY: 80 AN XY: 74370

Gnomad4 AFR AF: 0.00359

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000474 Hom.: 0

Bravo AF: 0.00121

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IGHMBP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Jan 31, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	1.2
Dann	Benign	0.68

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: rs146217031; hg19: chr11-68675632; COSMIC: COSV54825199; COSMIC: COSV54825199;