11-68936796-C-T

Variant names:

• chr11-68936796-C-T
• rs546382
• NM_002180.3:c.2316C>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.2316C>T​(p.Ser772Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,613,750 control chromosomes in the GnomAD database, including 74,656 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S772S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.25 (5440 hom., cov: 33)
  • Exomes 𝑓: 0.30 (69216 hom.)
• Consequence: IGHMBP2 NM_002180.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -2.89
• Publications: 40 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=-0.56).
• BP6: Variant 11-68936796-C-T is Benign according to our data. Variant chr11-68936796-C-T is described in ClinVar as Benign. ClinVar VariationId is 258570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.439 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.2316C>T	p.Ser772Ser	synonymous	Exon 13 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.2316C>T	p.Ser772Ser	synonymous	Exon 13 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000925063.1		c.2133C>T	p.Ser711Ser	synonymous	Exon 12 of 14	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.2316C>T	p.Ser772Ser	synonymous	Exon 13 of 14	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37943 AN: 152068 Hom.: 5445 Cov.: 33

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.291 AC: 72929 AN: 250902 AF XY: 0.307

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.368

Gnomad EAS exome AF: 0.196

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.296

GnomAD4 exome AF: 0.300 AC: 438806 AN: 1461564 Hom.: 69216 Cov.: 46 AF XY: 0.308 AC XY: 223695 AN XY: 727106

African (AFR) AF: 0.121 AC: 4040 AN: 33480

American (AMR) AF: 0.132 AC: 5916 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 9501 AN: 26136

East Asian (EAS) AF: 0.215 AC: 8525 AN: 39698

South Asian (SAS) AF: 0.456 AC: 39346 AN: 86254

European-Finnish (FIN) AF: 0.376 AC: 20028 AN: 53210

Middle Eastern (MID) AF: 0.351 AC: 2022 AN: 5766

European-Non Finnish (NFE) AF: 0.298 AC: 331633 AN: 1111904

Other (OTH) AF: 0.295 AC: 17795 AN: 60394

GnomAD4 genome AF: 0.249 AC: 37938 AN: 152186 Hom.: 5440 Cov.: 33 AF XY: 0.254 AC XY: 18924 AN XY: 74402

African (AFR) AF: 0.128 AC: 5337 AN: 41552

American (AMR) AF: 0.181 AC: 2764 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1308 AN: 3470

East Asian (EAS) AF: 0.197 AC: 1017 AN: 5172

South Asian (SAS) AF: 0.454 AC: 2194 AN: 4828

European-Finnish (FIN) AF: 0.366 AC: 3868 AN: 10582

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20705 AN: 67980

Other (OTH) AF: 0.237 AC: 501 AN: 2112

Alfa AF: 0.279 Hom.: 16122

Bravo AF: 0.225

Asia WGS AF: 0.302 AC: 1048 AN: 3478

EpiCase AF: 0.303

EpiControl AF: 0.310

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Autosomal recessive distal spinal muscular atrophy 1 (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	-0.56
CADD	Benign	0.31
DANN	Benign	0.89
PhyloP100		-2.9
Mutation Taster		=100/0	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: rs546382; hg19: chr11-68704264; COSMIC: COSV54820847; COSMIC: COSV54820847;