rs148157556

Variant names:

• chr11-68929226-C-T
• rs148157556
• NM_002180.3:c.1104C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-68929226-C-T
• chr11-68929226-C-A

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.1104C>T​(p.Tyr368Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00661 in 1,613,790 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: 32)
  • Exomes 𝑓: 0.0067 (74 hom.)
• Consequence: IGHMBP2 NM_002180.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.44
• 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=-0.49).
• BP6: Variant 11-68929226-C-T is Benign according to our data. Variant chr11-68929226-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00546 (832/152304) while in subpopulation AMR AF = 0.00889 (136/15302). AF 95% confidence interval is 0.00767. There are 6 homozygotes in GnomAd4. There are 407 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	NM_002180.3	MANE Select	c.1104C>T	p.Tyr368Tyr	synonymous	Exon 8 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.1104C>T	p.Tyr368Tyr	synonymous	Exon 8 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000925063.1		c.1104C>T	p.Tyr368Tyr	synonymous	Exon 8 of 14	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.1104C>T	p.Tyr368Tyr	synonymous	Exon 8 of 14	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes AF: 0.00541 AC: 823 AN: 152186 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.00328

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00714

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00678 AC: 1702 AN: 251104 AF XY: 0.00715

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00705

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.00337

Gnomad FIN exome AF: 0.00295

Gnomad NFE exome AF: 0.00763

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00672 AC: 9828 AN: 1461486 Hom.: 74 Cov.: 32 AF XY: 0.00681 AC XY: 4952 AN XY: 727086

African (AFR) AF: 0.000836 AC: 28 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 475 AN: 26136

East Asian (EAS) AF: 0.00229 AC: 91 AN: 39698

South Asian (SAS) AF: 0.00679 AC: 586 AN: 86258

European-Finnish (FIN) AF: 0.00277 AC: 147 AN: 53030

Middle Eastern (MID) AF: 0.0267 AC: 154 AN: 5766

European-Non Finnish (NFE) AF: 0.00679 AC: 7550 AN: 1112004

Other (OTH) AF: 0.00810 AC: 489 AN: 60390

GnomAD4 genome AF: 0.00546 AC: 832 AN: 152304 Hom.: 6 Cov.: 32 AF XY: 0.00547 AC XY: 407 AN XY: 74468

African (AFR) AF: 0.00132 AC: 55 AN: 41566

American (AMR) AF: 0.00889 AC: 136 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 46 AN: 3472

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5178

South Asian (SAS) AF: 0.00746 AC: 36 AN: 4824

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00717 AC: 488 AN: 68026

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

Alfa AF: 0.00659 Hom.: 7

Bravo AF: 0.00550

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.00900

EpiControl AF: 0.00966

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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	-0.49
CADD	Benign	2.4
DANN	Benign	0.43
PhyloP100		3.4
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148157556; hg19: chr11-68696694;