rs2236654

Variant names:

• chr11-68936560-C-T
• rs2236654
• NM_002180.3:c.2080C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-68936560-C-T
• chr11-68936560-C-A

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.2080C>T​(p.Arg694Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,611,560 control chromosomes in the GnomAD database, including 42,150 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R694Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.20 (3353 hom., cov: 33)
  • Exomes 𝑓: 0.22 (38797 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.319
• Publications: 30 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005527556).
• BP6: Variant 11-68936560-C-T is Benign according to our data. Variant chr11-68936560-C-T is described in ClinVar as Benign. ClinVar VariationId is 258567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.243 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.2080C>T	p.Arg694Trp	missense	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.2080C>T	p.Arg694Trp	missense	Exon 13 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000925063.1		c.1897C>T	p.Arg633Trp	missense	Exon 12 of 14	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.2080C>T	p.Arg694Trp	missense	Exon 13 of 14	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30599 AN: 152002 Hom.: 3352 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.0297

Gnomad SAS AF: 0.0678

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.255

GnomAD2 exomes AF: 0.188 AC: 46754 AN: 249024 AF XY: 0.187

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.276

Gnomad EAS exome AF: 0.0294

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.247

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.224 AC: 326345 AN: 1459440 Hom.: 38797 Cov.: 62 AF XY: 0.219 AC XY: 159223 AN XY: 725868

African (AFR) AF: 0.174 AC: 5802 AN: 33386

American (AMR) AF: 0.186 AC: 8291 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 7242 AN: 26076

East Asian (EAS) AF: 0.0308 AC: 1223 AN: 39682

South Asian (SAS) AF: 0.0782 AC: 6742 AN: 86216

European-Finnish (FIN) AF: 0.134 AC: 7028 AN: 52644

Middle Eastern (MID) AF: 0.223 AC: 1284 AN: 5762

European-Non Finnish (NFE) AF: 0.248 AC: 275690 AN: 1110778

Other (OTH) AF: 0.216 AC: 13043 AN: 60298

GnomAD4 genome AF: 0.201 AC: 30602 AN: 152120 Hom.: 3353 Cov.: 33 AF XY: 0.194 AC XY: 14419 AN XY: 74384

African (AFR) AF: 0.170 AC: 7055 AN: 41492

American (AMR) AF: 0.209 AC: 3189 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 972 AN: 3466

East Asian (EAS) AF: 0.0298 AC: 154 AN: 5174

South Asian (SAS) AF: 0.0672 AC: 324 AN: 4822

European-Finnish (FIN) AF: 0.124 AC: 1319 AN: 10600

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

European-Non Finnish (NFE) AF: 0.246 AC: 16718 AN: 67962

Other (OTH) AF: 0.252 AC: 532 AN: 2110

Alfa AF: 0.230 Hom.: 17714

Bravo AF: 0.211

TwinsUK AF: 0.248 AC: 921

ALSPAC AF: 0.245 AC: 945

ESP6500AA AF: 0.174 AC: 766

ESP6500EA AF: 0.248 AC: 2129

ExAC AF: 0.188 AC: 22756

Asia WGS AF: 0.0700 AC: 248 AN: 3478

EpiCase AF: 0.249

EpiControl AF: 0.255

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Autosomal recessive distal spinal muscular atrophy 1 (3)
-	-	2	not provided (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
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.32
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.060	T
Polyphen		0.013	B
Vest4		0.047
MPC		0.20
ClinPred		0.038	T
GERP RS		3.5
PromoterAI		-0.20	Neutral
Varity_R		0.071
gMVP		0.34
Mutation Taster		=89/11	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: rs2236654; hg19: chr11-68704028; COSMIC: COSV54820138; COSMIC: COSV54820138;