chr11-68914852-C-T

Variant names:

• chr11-68914852-C-T
• rs76707931
• NM_002180.3:c.741C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002180.3(IGHMBP2):​c.741C>T​(p.Ala247Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,614,250 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (74 hom.)
• Consequence: IGHMBP2 NM_002180.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -7.86
• Publications: 5 publications found

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]

IGHMBP2 Gene-Disease associations (from GenCC):

• autosomal recessive distal spinal muscular atrophy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease axonal type 2S

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary peripheral neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 11-68914852-C-T is Benign according to our data. Variant chr11-68914852-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.86 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00549 (837/152360) while in subpopulation AMR AF = 0.00896 (137/15298). AF 95% confidence interval is 0.00773. There are 6 homozygotes in GnomAd4. There are 411 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002180.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	NM_002180.3	MANE Select	c.741C>T	p.Ala247Ala	synonymous	Exon 6 of 15	NP_002171.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.741C>T	p.Ala247Ala	synonymous	Exon 6 of 15	ENSP00000255078.4
	IGHMBP2	ENST00000675615.1		c.741C>T	p.Ala247Ala	synonymous	Exon 6 of 14	ENSP00000502413.1
	IGHMBP2	ENST00000675464.1		c.30C>T	p.Ala10Ala	synonymous	Exon 1 of 2	ENSP00000502650.1

Frequencies

GnomAD3 genomes AF: 0.00544 AC: 828 AN: 152242 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00365

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00716

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00682 AC: 1715 AN: 251362 AF XY: 0.00722

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00705

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.00375

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00766

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00674 AC: 9854 AN: 1461890 Hom.: 74 Cov.: 32 AF XY: 0.00683 AC XY: 4965 AN XY: 727244

African (AFR) AF: 0.000866 AC: 29 AN: 33480

American (AMR) AF: 0.00689 AC: 308 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 475 AN: 26134

East Asian (EAS) AF: 0.00244 AC: 97 AN: 39700

South Asian (SAS) AF: 0.00687 AC: 593 AN: 86258

European-Finnish (FIN) AF: 0.00277 AC: 148 AN: 53420

Middle Eastern (MID) AF: 0.0267 AC: 154 AN: 5768

European-Non Finnish (NFE) AF: 0.00680 AC: 7562 AN: 1112010

Other (OTH) AF: 0.00808 AC: 488 AN: 60396

GnomAD4 genome AF: 0.00549 AC: 837 AN: 152360 Hom.: 6 Cov.: 33 AF XY: 0.00552 AC XY: 411 AN XY: 74506

African (AFR) AF: 0.00135 AC: 56 AN: 41588

American (AMR) AF: 0.00896 AC: 137 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.00366 AC: 19 AN: 5188

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4830

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00719 AC: 489 AN: 68042

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00597 Hom.: 3

Bravo AF: 0.00556

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.00900

EpiControl AF: 0.00966

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Autosomal recessive distal spinal muscular atrophy 1 (1)
-	-	1	Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.8
DANN	Benign	0.65
PhyloP100		-7.9
PromoterAI		0.0059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs76707931; hg19: chr11-68682320;