rs771853806

chr11-68904016-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002180.3(IGHMBP2):c.64G>T(p.Asp22Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,397,686 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D22E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.48

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGHMBP2	NM_002180.3	c.64G>T	p.Asp22Tyr	missense_variant	1/15	ENST00000255078.8
IGHMBP2	XM_047426881.1	c.64G>T	p.Asp22Tyr	missense_variant	1/15
IGHMBP2	XM_017017671.3	c.64G>T	p.Asp22Tyr	missense_variant	1/12
IGHMBP2	XM_005273976.3	c.64G>T	p.Asp22Tyr	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.64G>T	p.Asp22Tyr	missense_variant	1/15	1	NM_002180.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1397686 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 689412

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000149 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 10, 2018

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces aspartic acid with tyrosine at codon 22 of the IGHMBP2 protein (p.Asp22Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant has not been reported in the literature in individuals with IGHMBP2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.89	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.89	P;.
Vest4		0.43
MutPred		0.38		Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);
MVP		0.95
MPC		0.62
ClinPred		0.97	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.58

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: rs771853806; hg19: chr11-68671484; COSMIC: COSV99661906; COSMIC: COSV99661906;