NM_002180.3:c.-2C>T

Variant names:

• chr11-68903951-C-T
• rs4930624
• NM_002180.3:c.-2C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002180.3(IGHMBP2):​c.-2C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,569,878 control chromosomes in the GnomAD database, including 41,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3026 hom., cov: 35)
  • Exomes 𝑓: 0.23 (38756 hom.)
• Consequence: IGHMBP2 NM_002180.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0100
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 11-68903951-C-T is Benign according to our data. Variant chr11-68903951-C-T is described in ClinVar as Benign. ClinVar VariationId is 258555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.246 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.-2C>T		5_prime_UTR	Exon 1 of 15	NP_002171.2	P38935
	MRPL21	NM_181514.2	MANE Select	c.-141G>A		upstream_gene	N/A	NP_852615.1	Q7Z2W9-1
	MRPL21	NM_181515.2		c.-409G>A		upstream_gene	N/A	NP_852616.1	Q7Z2W9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.-2C>T		5_prime_UTR	Exon 1 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000925063.1		c.-2C>T		5_prime_UTR	Exon 1 of 14	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.-2C>T		5_prime_UTR	Exon 1 of 14	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27968 AN: 152008 Hom.: 3023 Cov.: 35

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.0607

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.244

GnomAD2 exomes AF: 0.187 AC: 33258 AN: 177460 AF XY: 0.186

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.0257

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.265

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.225 AC: 319618 AN: 1417752 Hom.: 38756 Cov.: 40 AF XY: 0.221 AC XY: 155113 AN XY: 701912

African (AFR) AF: 0.100 AC: 3243 AN: 32322

American (AMR) AF: 0.188 AC: 7055 AN: 37454

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 7194 AN: 25396

East Asian (EAS) AF: 0.0273 AC: 1013 AN: 37130

South Asian (SAS) AF: 0.0706 AC: 5817 AN: 82378

European-Finnish (FIN) AF: 0.133 AC: 6564 AN: 49290

Middle Eastern (MID) AF: 0.217 AC: 1239 AN: 5700

European-Non Finnish (NFE) AF: 0.252 AC: 274957 AN: 1089384

Other (OTH) AF: 0.214 AC: 12536 AN: 58698

GnomAD4 genome AF: 0.184 AC: 27984 AN: 152126 Hom.: 3026 Cov.: 35 AF XY: 0.176 AC XY: 13124 AN XY: 74374

African (AFR) AF: 0.103 AC: 4282 AN: 41508

American (AMR) AF: 0.207 AC: 3174 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 995 AN: 3470

East Asian (EAS) AF: 0.0244 AC: 125 AN: 5132

South Asian (SAS) AF: 0.0601 AC: 290 AN: 4824

European-Finnish (FIN) AF: 0.124 AC: 1315 AN: 10610

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16957 AN: 67956

Other (OTH) AF: 0.241 AC: 509 AN: 2116

Alfa AF: 0.237 Hom.: 3094

Bravo AF: 0.190

Asia WGS AF: 0.0550 AC: 192 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Autosomal recessive distal spinal muscular atrophy 1 (2)
-	-	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	-0.53
CADD	Benign	15
DANN	Uncertain	0.99
PhyloP100		0.010
PromoterAI		0.0082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=300/0	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: rs4930624; hg19: chr11-68671419;