rs34617762

Variant names:

• chr11-68906162-C-T
• rs34617762
• NM_002180.3:c.180C>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.180C>T​(p.Tyr60Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,126 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (17 hom., cov: 32)
  • Exomes 𝑓: 0.011 (124 hom.)
• Consequence: IGHMBP2 NM_002180.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.67
• Publications: 6 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 11-68906162-C-T is Benign according to our data. Variant chr11-68906162-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00944 (1437/152282) while in subpopulation NFE AF = 0.0127 (867/68024). AF 95% confidence interval is 0.012. There are 17 homozygotes in GnomAd4. There are 750 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	NM_002180.3	MANE Select	c.180C>T	p.Tyr60Tyr	synonymous	Exon 2 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.180C>T	p.Tyr60Tyr	synonymous	Exon 2 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000925063.1		c.180C>T	p.Tyr60Tyr	synonymous	Exon 2 of 14	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.180C>T	p.Tyr60Tyr	synonymous	Exon 2 of 14	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes AF: 0.00944 AC: 1437 AN: 152164 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00950 AC: 2390 AN: 251482 AF XY: 0.0104

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00653

Gnomad ASJ exome AF: 0.00734

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0113 AC: 16575 AN: 1461844 Hom.: 124 Cov.: 31 AF XY: 0.0114 AC XY: 8298 AN XY: 727228

African (AFR) AF: 0.00215 AC: 72 AN: 33478

American (AMR) AF: 0.00722 AC: 323 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00781 AC: 204 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00329 AC: 284 AN: 86252

European-Finnish (FIN) AF: 0.0176 AC: 941 AN: 53408

Middle Eastern (MID) AF: 0.0167 AC: 96 AN: 5760

European-Non Finnish (NFE) AF: 0.0126 AC: 13998 AN: 1111992

Other (OTH) AF: 0.0108 AC: 654 AN: 60394

GnomAD4 genome AF: 0.00944 AC: 1437 AN: 152282 Hom.: 17 Cov.: 32 AF XY: 0.0101 AC XY: 750 AN XY: 74456

African (AFR) AF: 0.00258 AC: 107 AN: 41548

American (AMR) AF: 0.00987 AC: 151 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.0209 AC: 222 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0127 AC: 867 AN: 68024

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.00992 Hom.: 6

Bravo AF: 0.00864

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0170

EpiControl AF: 0.0174

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.4
DANN	Benign	0.90
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34617762; hg19: chr11-68673630;