11-68934480-C-T

Variant names:

• chr11-68934480-C-T
• rs11228413
• NM_002180.3:c.1554C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002180.3(IGHMBP2):​c.1554C>T​(p.Val518Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,608,376 control chromosomes in the GnomAD database, including 41,992 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3352 hom., cov: 33)
  • Exomes 𝑓: 0.22 (38640 hom.)
• Consequence: IGHMBP2 NM_002180.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.877
• Publications: 19 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: Ambry Genetics, Laboratory for Molecular Medicine, Orphanet, 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=-0.61).
• BP6: Variant 11-68934480-C-T is Benign according to our data. Variant chr11-68934480-C-T is described in ClinVar as Benign. ClinVar VariationId is 258560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.877 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	NM_002180.3	MANE Select	c.1554C>T	p.Val518Val	synonymous	Exon 11 of 15	NP_002171.2	P38935

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.1554C>T	p.Val518Val	synonymous	Exon 11 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000541229.5	TSL:1	n.249C>T		non_coding_transcript_exon	Exon 2 of 4
	IGHMBP2	ENST00000925063.1		c.1371C>T	p.Val457Val	synonymous	Exon 10 of 14	ENSP00000595122.1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30606 AN: 152126 Hom.: 3350 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.0300

Gnomad SAS AF: 0.0675

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.255

GnomAD2 exomes AF: 0.186 AC: 45258 AN: 243508 AF XY: 0.185

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.184

Gnomad ASJ exome AF: 0.274

Gnomad EAS exome AF: 0.0291

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.223 AC: 324909 AN: 1456132 Hom.: 38640 Cov.: 32 AF XY: 0.219 AC XY: 158478 AN XY: 723986

African (AFR) AF: 0.173 AC: 5778 AN: 33348

American (AMR) AF: 0.185 AC: 8197 AN: 44246

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 7213 AN: 26034

East Asian (EAS) AF: 0.0308 AC: 1219 AN: 39598

South Asian (SAS) AF: 0.0779 AC: 6655 AN: 85404

European-Finnish (FIN) AF: 0.133 AC: 7058 AN: 53184

Middle Eastern (MID) AF: 0.223 AC: 1285 AN: 5766

European-Non Finnish (NFE) AF: 0.248 AC: 274505 AN: 1108356

Other (OTH) AF: 0.216 AC: 12999 AN: 60196

GnomAD4 genome AF: 0.201 AC: 30618 AN: 152244 Hom.: 3352 Cov.: 33 AF XY: 0.194 AC XY: 14425 AN XY: 74446

African (AFR) AF: 0.170 AC: 7074 AN: 41546

American (AMR) AF: 0.208 AC: 3184 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 971 AN: 3470

East Asian (EAS) AF: 0.0301 AC: 156 AN: 5186

South Asian (SAS) AF: 0.0669 AC: 323 AN: 4828

European-Finnish (FIN) AF: 0.124 AC: 1321 AN: 10614

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16718 AN: 67996

Other (OTH) AF: 0.252 AC: 532 AN: 2112

Alfa AF: 0.233 Hom.: 3030

Bravo AF: 0.211

Asia WGS AF: 0.0700 AC: 248 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Autosomal recessive distal spinal muscular atrophy 1 (3)
-	-	2	not provided (2)
-	-	1	Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2S (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.8
DANN	Benign	0.90
PhyloP100		-0.88
Mutation Taster		=97/3	polymorphism (auto)

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: rs11228413; hg19: chr11-68701948; COSMIC: COSV54824692; COSMIC: COSV54824692;