rs17612126

Variant names:

• chr11-68938206-C-A
• rs17612126
• NM_002180.3:c.2636C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-68938206-C-A
• chr11-68938206-C-G
• chr11-68938206-C-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.2636C>A​(p.Thr879Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 1,613,734 control chromosomes in the GnomAD database, including 63,713 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T879M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.23 (4935 hom., cov: 32)
  • Exomes 𝑓: 0.28 (58778 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:13
• Conservation: PhyloP100: -0.292
• Publications: 43 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: Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, 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=3.3271313E-4).
• BP6: Variant 11-68938206-C-A is Benign according to our data. Variant chr11-68938206-C-A is described in ClinVar as Benign. ClinVar VariationId is 194368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.39 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.2636C>A	p.Thr879Lys	missense	Exon 14 of 15	NP_002171.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.2636C>A	p.Thr879Lys	missense	Exon 14 of 15	ENSP00000255078.4
	IGHMBP2	ENST00000544521.1	TSL:1	n.467C>A		non_coding_transcript_exon	Exon 1 of 2
	IGHMBP2	ENST00000925063.1		c.2453C>A	p.Thr818Lys	missense	Exon 13 of 14	ENSP00000595122.1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34238 AN: 152000 Hom.: 4928 Cov.: 32

Gnomad AFR AF: 0.0649

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.219

GnomAD2 exomes AF: 0.264 AC: 66271 AN: 251418 AF XY: 0.256

Gnomad AFR exome AF: 0.0622

Gnomad AMR exome AF: 0.464

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.245

Gnomad FIN exome AF: 0.247

Gnomad NFE exome AF: 0.272

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.277 AC: 404789 AN: 1461616 Hom.: 58778 Cov.: 38 AF XY: 0.273 AC XY: 198447 AN XY: 727156

African (AFR) AF: 0.0517 AC: 1732 AN: 33478

American (AMR) AF: 0.457 AC: 20435 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3601 AN: 26136

East Asian (EAS) AF: 0.255 AC: 10105 AN: 39700

South Asian (SAS) AF: 0.183 AC: 15764 AN: 86254

European-Finnish (FIN) AF: 0.246 AC: 13085 AN: 53288

Middle Eastern (MID) AF: 0.205 AC: 1180 AN: 5760

European-Non Finnish (NFE) AF: 0.291 AC: 324000 AN: 1111896

Other (OTH) AF: 0.247 AC: 14887 AN: 60382

GnomAD4 genome AF: 0.225 AC: 34253 AN: 152118 Hom.: 4935 Cov.: 32 AF XY: 0.228 AC XY: 16948 AN XY: 74346

African (AFR) AF: 0.0648 AC: 2690 AN: 41512

American (AMR) AF: 0.398 AC: 6078 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3468

East Asian (EAS) AF: 0.245 AC: 1264 AN: 5158

South Asian (SAS) AF: 0.177 AC: 856 AN: 4830

European-Finnish (FIN) AF: 0.265 AC: 2800 AN: 10578

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19205 AN: 67986

Other (OTH) AF: 0.218 AC: 460 AN: 2110

Alfa AF: 0.252 Hom.: 14826

Bravo AF: 0.231

TwinsUK AF: 0.297 AC: 1100

ALSPAC AF: 0.303 AC: 1169

ESP6500AA AF: 0.0777 AC: 342

ESP6500EA AF: 0.278 AC: 2387

ExAC AF: 0.250 AC: 30305

Asia WGS AF: 0.197 AC: 684 AN: 3478

EpiCase AF: 0.280

EpiControl AF: 0.270

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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)
-	1	-	Neuronopathy, distal hereditary motor, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.24
DANN	Benign	0.81
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.00033	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.29
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.21
Sift	Benign	0.90	T
Sift4G	Benign	1.0	T
Polyphen		0.21	B
Vest4		0.050
MPC		0.23
ClinPred		0.0042	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.20
Mutation Taster		=97/3	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: rs17612126; hg19: chr11-68705674; COSMIC: COSV54822413; COSMIC: COSV54822413;