rs1249463

Variant names:

• chr11-68904009-T-C
• rs1249463
• NM_002180.3:c.57T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-68904009-T-C
• chr11-68904009-T-G

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.57T>C​(p.Leu19Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.814 in 1,550,292 control chromosomes in the GnomAD database, including 517,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44837 hom., cov: 34)
  • Exomes 𝑓: 0.82 (473052 hom.)
• Consequence: IGHMBP2 NM_002180.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.0150
• Publications: 23 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]

MRPL21 (HGNC:14479): (mitochondrial ribosomal protein L21) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. Multiple transcript variants encoding different isoforms were identified through sequence analysis although some may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-68904009-T-C is Benign according to our data. Variant chr11-68904009-T-C is described in ClinVar as Benign. ClinVar VariationId is 258575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.015 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.837 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.57T>C	p.Leu19Leu	synonymous	Exon 1 of 15	NP_002171.2
	MRPL21	NM_181514.2	MANE Select	c.-199A>G		upstream_gene	N/A	NP_852615.1
	MRPL21	NM_181515.2		c.-467A>G		upstream_gene	N/A	NP_852616.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.57T>C	p.Leu19Leu	synonymous	Exon 1 of 15	ENSP00000255078.4
	IGHMBP2	ENST00000925063.1		c.57T>C	p.Leu19Leu	synonymous	Exon 1 of 14	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.57T>C	p.Leu19Leu	synonymous	Exon 1 of 14	ENSP00000502413.1

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115447 AN: 152028 Hom.: 44809 Cov.: 34

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.910

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.796

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.758

Gnomad MID AF: 0.803

Gnomad NFE AF: 0.843

Gnomad OTH AF: 0.788

GnomAD2 exomes AF: 0.769 AC: 118247 AN: 153684 AF XY: 0.772

Gnomad AFR exome AF: 0.618

Gnomad AMR exome AF: 0.799

Gnomad ASJ exome AF: 0.797

Gnomad EAS exome AF: 0.472

Gnomad FIN exome AF: 0.757

Gnomad NFE exome AF: 0.844

Gnomad OTH exome AF: 0.795

GnomAD4 exome AF: 0.820 AC: 1146146 AN: 1398142 Hom.: 473052 Cov.: 59 AF XY: 0.818 AC XY: 564363 AN XY: 689706

African (AFR) AF: 0.625 AC: 19744 AN: 31584

American (AMR) AF: 0.798 AC: 28508 AN: 35734

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 20067 AN: 25162

East Asian (EAS) AF: 0.533 AC: 19059 AN: 35736

South Asian (SAS) AF: 0.746 AC: 59210 AN: 79388

European-Finnish (FIN) AF: 0.757 AC: 36394 AN: 48086

Middle Eastern (MID) AF: 0.819 AC: 4633 AN: 5654

European-Non Finnish (NFE) AF: 0.846 AC: 912873 AN: 1078824

Other (OTH) AF: 0.788 AC: 45658 AN: 57974

GnomAD4 genome AF: 0.759 AC: 115526 AN: 152150 Hom.: 44837 Cov.: 34 AF XY: 0.758 AC XY: 56397 AN XY: 74388

African (AFR) AF: 0.628 AC: 26050 AN: 41508

American (AMR) AF: 0.826 AC: 12644 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 2762 AN: 3470

East Asian (EAS) AF: 0.488 AC: 2512 AN: 5144

South Asian (SAS) AF: 0.730 AC: 3520 AN: 4822

European-Finnish (FIN) AF: 0.758 AC: 8040 AN: 10608

Middle Eastern (MID) AF: 0.801 AC: 234 AN: 292

European-Non Finnish (NFE) AF: 0.843 AC: 57273 AN: 67978

Other (OTH) AF: 0.786 AC: 1661 AN: 2114

Alfa AF: 0.817 Hom.: 33806

Bravo AF: 0.758

Asia WGS AF: 0.622 AC: 2162 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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	-0.78
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		0.015
PromoterAI		0.0040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs1249463; hg19: chr11-68671477; COSMIC: COSV54826298; COSMIC: COSV54826298;