rs2228206

chr11-68906205-G-Achr11-68906205-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002180.3(IGHMBP2):c.223G>A(p.Ala75Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,614,020 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A75V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0085 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (16 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.47

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 (MetaRNN=0.0032362044).
• BP6: Variant 11-68906205-G-A is Benign according to our data. Variant chr11-68906205-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00853 (1299/152282) while in subpopulation AFR AF= 0.0296 (1230/41560). AF 95% confidence interval is 0.0282. There are 18 homozygotes in gnomad4. There are 611 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGHMBP2	NM_002180.3	c.223G>A	p.Ala75Thr	missense_variant	2/15	ENST00000255078.8
IGHMBP2	XM_047426881.1	c.223G>A	p.Ala75Thr	missense_variant	2/15
IGHMBP2	XM_017017671.3	c.223G>A	p.Ala75Thr	missense_variant	2/12
IGHMBP2	XM_005273976.3	c.223G>A	p.Ala75Thr	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.223G>A	p.Ala75Thr	missense_variant	2/15	1	NM_002180.3	P1

Frequencies

GnomAD3 genomes AF: 0.00855 AC: 1301 AN: 152164 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00234 AC: 588 AN: 251468 Hom.: 9 AF XY: 0.00171 AC XY: 232 AN XY: 135908

Gnomad AFR exome AF: 0.0320

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000854 AC: 1249 AN: 1461738 Hom.: 16 Cov.: 31 AF XY: 0.000760 AC XY: 553 AN XY: 727164

Gnomad4 AFR exome AF: 0.0304

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00853 AC: 1299 AN: 152282 Hom.: 18 Cov.: 32 AF XY: 0.00821 AC XY: 611 AN XY: 74464

Gnomad4 AFR AF: 0.0296

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00146 Hom.: 6

Bravo AF: 0.00970

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00278 AC: 338

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 13, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	13
Dann	Benign	0.79
DEOGEN2	Benign	0.063	T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.46	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.064
Sift	Benign	0.66	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.39	B;.
Vest4		0.16
MVP		0.88
MPC		0.19
ClinPred		0.0061	T
GERP RS		1.7
Varity_R		0.051
gMVP		0.22

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: rs2228206; hg19: chr11-68673673;