11-68903928-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_002180.3(IGHMBP2):c.-25C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,595,628 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 0.00032 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: IGHMBP2 NM_002180.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.216

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 11-68903928-C-T is Benign according to our data. Variant chr11-68903928-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 389694.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000322 (49/152254) while in subpopulation AMR AF= 0.00222 (34/15286). AF 95% confidence interval is 0.00164. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGHMBP2	NM_002180.3	c.-25C>T		5_prime_UTR_variant	1/15	ENST00000255078.8
IGHMBP2	XM_005273976.3	c.-25C>T		5_prime_UTR_variant	1/9
IGHMBP2	XM_017017671.3	c.-25C>T		5_prime_UTR_variant	1/12
IGHMBP2	XM_047426881.1	c.-25C>T		5_prime_UTR_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.-25C>T		5_prime_UTR_variant	1/15	1	NM_002180.3	P1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152254 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000216 AC: 45 AN: 208146 Hom.: 0 AF XY: 0.000211 AC XY: 24 AN XY: 113918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000693

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.000188

GnomAD4 exome AF: 0.000201 AC: 290 AN: 1443374 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 144 AN XY: 716668

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.000601

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000772

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.000177

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.000218

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152254 Hom.: 0 Cov.: 35 AF XY: 0.000417 AC XY: 31 AN XY: 74394

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000230

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 20, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	7.9
Dann	Benign	0.81

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: rs780273172; hg19: chr11-68671396;