11-68934444-C-T

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.1538-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00427 in 1,578,120 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (73 hom.)
• Consequence: IGHMBP2 NM_002180.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.81

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 (BayesDel_noAF=-0.88).
• BP6: Variant 11-68934444-C-T is Benign according to our data. Variant chr11-68934444-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68934444-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00278 (424/152324) while in subpopulation SAS AF= 0.0209 (101/4822). AF 95% confidence interval is 0.0176. There are 3 homozygotes in gnomad4. There are 222 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGHMBP2	NM_002180.3	c.1538-20C>T		intron_variant		ENST00000255078.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.1538-20C>T		intron_variant		1	NM_002180.3	P1

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152206 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0218

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00267

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00620 AC: 1353 AN: 218312 Hom.: 23 AF XY: 0.00778 AC XY: 916 AN XY: 117666

Gnomad AFR exome AF: 0.000897

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.000124

Gnomad SAS exome AF: 0.0293

Gnomad FIN exome AF: 0.000946

Gnomad NFE exome AF: 0.00324

Gnomad OTH exome AF: 0.00583

GnomAD4 exome AF: 0.00443 AC: 6310 AN: 1425796 Hom.: 73 Cov.: 28 AF XY: 0.00531 AC XY: 3763 AN XY: 708712

Gnomad4 AFR exome AF: 0.000981

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.000442

Gnomad4 SAS exome AF: 0.0283

Gnomad4 FIN exome AF: 0.000939

Gnomad4 NFE exome AF: 0.00275

Gnomad4 OTH exome AF: 0.00544

GnomAD4 genome AF: 0.00278 AC: 424 AN: 152324 Hom.: 3 Cov.: 33 AF XY: 0.00298 AC XY: 222 AN XY: 74478

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00268

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00434 Hom.: 1

Bravo AF: 0.00254

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Likely 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.27
Dann	Benign	0.73

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: rs147148090; hg19: chr11-68701912;