chr11-68911494-T-C

Variant names:

• chr11-68911494-T-C
• rs560096
• NM_002180.3:c.602T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_002180.3(IGHMBP2):​c.602T>C​(p.Leu201Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 1,613,828 control chromosomes in the GnomAD database, including 538,558 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. L201F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.76 (45193 hom., cov: 31)
  • Exomes 𝑓: 0.82 (493365 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0320
• Publications: 54 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_002180.3
• BP4: Computational evidence support a benign effect (MetaRNN=6.9917377E-7).
• BP6: Variant 11-68911494-T-C is Benign according to our data. Variant chr11-68911494-T-C is described in ClinVar as Benign. ClinVar VariationId is 258576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.837 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.602T>C	p.Leu201Ser	missense	Exon 5 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.602T>C	p.Leu201Ser	missense	Exon 5 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000925063.1		c.602T>C	p.Leu201Ser	missense	Exon 5 of 14	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.602T>C	p.Leu201Ser	missense	Exon 5 of 14	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes AF: 0.763 AC: 116004 AN: 151978 Hom.: 45161 Cov.: 31

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.910

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.796

Gnomad EAS AF: 0.488

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.759

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.843

Gnomad OTH AF: 0.793

GnomAD2 exomes AF: 0.773 AC: 194369 AN: 251366 AF XY: 0.777

Gnomad AFR exome AF: 0.637

Gnomad AMR exome AF: 0.799

Gnomad ASJ exome AF: 0.798

Gnomad EAS exome AF: 0.481

Gnomad FIN exome AF: 0.761

Gnomad NFE exome AF: 0.839

Gnomad OTH exome AF: 0.795

GnomAD4 exome AF: 0.819 AC: 1196697 AN: 1461732 Hom.: 493365 Cov.: 49 AF XY: 0.817 AC XY: 594292 AN XY: 727172

African (AFR) AF: 0.637 AC: 21338 AN: 33478

American (AMR) AF: 0.799 AC: 35714 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 20850 AN: 26136

East Asian (EAS) AF: 0.531 AC: 21078 AN: 39694

South Asian (SAS) AF: 0.745 AC: 64259 AN: 86248

European-Finnish (FIN) AF: 0.758 AC: 40493 AN: 53410

Middle Eastern (MID) AF: 0.820 AC: 4723 AN: 5758

European-Non Finnish (NFE) AF: 0.846 AC: 940660 AN: 1111900

Other (OTH) AF: 0.788 AC: 47582 AN: 60388

GnomAD4 genome AF: 0.763 AC: 116087 AN: 152096 Hom.: 45193 Cov.: 31 AF XY: 0.762 AC XY: 56642 AN XY: 74350

African (AFR) AF: 0.641 AC: 26559 AN: 41464

American (AMR) AF: 0.829 AC: 12663 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 2758 AN: 3466

East Asian (EAS) AF: 0.488 AC: 2524 AN: 5170

South Asian (SAS) AF: 0.728 AC: 3513 AN: 4824

European-Finnish (FIN) AF: 0.759 AC: 8019 AN: 10570

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.843 AC: 57325 AN: 68008

Other (OTH) AF: 0.790 AC: 1662 AN: 2104

Alfa AF: 0.812 Hom.: 195528

Bravo AF: 0.762

TwinsUK AF: 0.842 AC: 3122

ALSPAC AF: 0.855 AC: 3297

ESP6500AA AF: 0.650 AC: 2862

ESP6500EA AF: 0.844 AC: 7250

ExAC AF: 0.771 AC: 93660

Asia WGS AF: 0.622 AC: 2165 AN: 3478

EpiCase AF: 0.844

EpiControl AF: 0.848

ClinVar

ClinVar submissions

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.7
DANN	Benign	0.31
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.077	T
MetaRNN	Benign	7.0e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.032
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.14
Sift	Benign	0.26	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.26
ClinPred		0.012	T
GERP RS		-1.6
Varity_R		0.24
gMVP		0.30
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: rs560096; hg19: chr11-68678962; COSMIC: COSV54822264; COSMIC: COSV54822264;