rs2228207

Variant names:

• chr11-68937012-G-A
• rs2228207
• NM_002180.3:c.2532G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-68937012-G-A
• chr11-68937012-G-C
• chr11-68937012-G-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.2532G>A​(p.Ala844Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,608,480 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A844A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0074 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (12 hom.)
• Consequence: IGHMBP2 NM_002180.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.817
• Publications: 0 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=-0.82).
• BP6: Variant 11-68937012-G-A is Benign according to our data. Variant chr11-68937012-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.817 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00738 (1124/152340) while in subpopulation AFR AF = 0.0261 (1087/41576). AF 95% confidence interval is 0.0249. There are 14 homozygotes in GnomAd4. There are 528 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.2532G>A	p.Ala844Ala	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.2532G>A	p.Ala844Ala	synonymous	Exon 13 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000925063.1		c.2349G>A	p.Ala783Ala	synonymous	Exon 12 of 14	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.2532G>A	p.Ala844Ala	synonymous	Exon 13 of 14	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes AF: 0.00735 AC: 1119 AN: 152222 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00195 AC: 460 AN: 235328 AF XY: 0.00154

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000956

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.000736 AC: 1071 AN: 1456140 Hom.: 12 Cov.: 35 AF XY: 0.000665 AC XY: 482 AN XY: 724410

African (AFR) AF: 0.0245 AC: 819 AN: 33432

American (AMR) AF: 0.00153 AC: 68 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49378

Middle Eastern (MID) AF: 0.00143 AC: 7 AN: 4910

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111660

Other (OTH) AF: 0.00156 AC: 94 AN: 60242

GnomAD4 genome AF: 0.00738 AC: 1124 AN: 152340 Hom.: 14 Cov.: 33 AF XY: 0.00709 AC XY: 528 AN XY: 74492

African (AFR) AF: 0.0261 AC: 1087 AN: 41576

American (AMR) AF: 0.00170 AC: 26 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00236 Hom.: 2

Bravo AF: 0.00849

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.1
DANN	Benign	0.62
PhyloP100		0.82
Mutation Taster		=100/0	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: rs2228207; hg19: chr11-68704480;