rs622082

Variant names:

• chr11-68936491-A-G
• rs622082
• NM_002180.3:c.2011A>G

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.2011A>G​(p.Thr671Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,613,488 control chromosomes in the GnomAD database, including 74,641 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. T671S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (5443 hom., cov: 33)
  • Exomes 𝑓: 0.30 (69198 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.58
• Publications: 64 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=2.5120378E-4).
• BP6: Variant 11-68936491-A-G is Benign according to our data. Variant chr11-68936491-A-G is described in ClinVar as Benign. ClinVar VariationId is 258566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.439 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.2011A>G	p.Thr671Ala	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.2011A>G	p.Thr671Ala	missense	Exon 13 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000925063.1		c.1828A>G	p.Thr610Ala	missense	Exon 12 of 14	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.2011A>G	p.Thr671Ala	missense	Exon 13 of 14	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37938 AN: 151982 Hom.: 5448 Cov.: 33

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.291 AC: 72856 AN: 250432 AF XY: 0.307

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.368

Gnomad EAS exome AF: 0.196

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.296

GnomAD4 exome AF: 0.300 AC: 438739 AN: 1461388 Hom.: 69198 Cov.: 54 AF XY: 0.308 AC XY: 223655 AN XY: 727002

African (AFR) AF: 0.120 AC: 4031 AN: 33480

American (AMR) AF: 0.132 AC: 5910 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 9501 AN: 26134

East Asian (EAS) AF: 0.215 AC: 8525 AN: 39700

South Asian (SAS) AF: 0.456 AC: 39348 AN: 86254

European-Finnish (FIN) AF: 0.377 AC: 19975 AN: 53038

Middle Eastern (MID) AF: 0.351 AC: 2024 AN: 5768

European-Non Finnish (NFE) AF: 0.298 AC: 331637 AN: 1111916

Other (OTH) AF: 0.295 AC: 17788 AN: 60380

GnomAD4 genome AF: 0.249 AC: 37933 AN: 152100 Hom.: 5443 Cov.: 33 AF XY: 0.254 AC XY: 18920 AN XY: 74356

African (AFR) AF: 0.128 AC: 5335 AN: 41528

American (AMR) AF: 0.180 AC: 2757 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1309 AN: 3470

East Asian (EAS) AF: 0.198 AC: 1018 AN: 5154

South Asian (SAS) AF: 0.455 AC: 2192 AN: 4814

European-Finnish (FIN) AF: 0.365 AC: 3866 AN: 10580

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20710 AN: 67958

Other (OTH) AF: 0.237 AC: 500 AN: 2108

Alfa AF: 0.287 Hom.: 21512

Bravo AF: 0.225

TwinsUK AF: 0.293 AC: 1086

ALSPAC AF: 0.300 AC: 1155

ESP6500AA AF: 0.127 AC: 559

ESP6500EA AF: 0.308 AC: 2645

ExAC AF: 0.298 AC: 36138

Asia WGS AF: 0.302 AC: 1047 AN: 3478

EpiCase AF: 0.303

EpiControl AF: 0.310

ClinVar

ClinVar submissions

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	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	0.053
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.0060
DANN	Benign	0.24
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.00025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.49	N
PhyloP100		-1.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.18
Sift	Benign	0.94	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.0090
MPC		0.19
ClinPred		0.00067	T
GERP RS		-6.7
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.25
Mutation Taster		=93/7	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: rs622082; hg19: chr11-68703959; COSMIC: COSV54820189; COSMIC: COSV54820189;