chr11-68914934-A-G

Variant names:

• chr11-68914934-A-G
• rs10896380
• NM_002180.3:c.823A>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.823A>G​(p.Ile275Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,613,918 control chromosomes in the GnomAD database, including 41,567 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3019 hom., cov: 32)
  • Exomes 𝑓: 0.22 (38548 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.47
• Publications: 37 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=0.0015553236).
• BP6: Variant 11-68914934-A-G is Benign according to our data. Variant chr11-68914934-A-G is described in ClinVar as Benign. ClinVar VariationId is 258577.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.823A>G	p.Ile275Val	missense	Exon 6 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.823A>G	p.Ile275Val	missense	Exon 6 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000925063.1		c.823A>G	p.Ile275Val	missense	Exon 6 of 14	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.823A>G	p.Ile275Val	missense	Exon 6 of 14	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28361 AN: 152074 Hom.: 3017 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.0236

Gnomad SAS AF: 0.0606

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.244

GnomAD2 exomes AF: 0.182 AC: 45868 AN: 251462 AF XY: 0.182

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.183

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.0239

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.247

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.222 AC: 323970 AN: 1461726 Hom.: 38548 Cov.: 35 AF XY: 0.217 AC XY: 158137 AN XY: 727210

African (AFR) AF: 0.119 AC: 3997 AN: 33478

American (AMR) AF: 0.184 AC: 8239 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 7254 AN: 26136

East Asian (EAS) AF: 0.0271 AC: 1075 AN: 39698

South Asian (SAS) AF: 0.0699 AC: 6030 AN: 86254

European-Finnish (FIN) AF: 0.133 AC: 7111 AN: 53418

Middle Eastern (MID) AF: 0.220 AC: 1270 AN: 5768

European-Non Finnish (NFE) AF: 0.248 AC: 276231 AN: 1111868

Other (OTH) AF: 0.211 AC: 12763 AN: 60384

GnomAD4 genome AF: 0.186 AC: 28372 AN: 152192 Hom.: 3019 Cov.: 32 AF XY: 0.179 AC XY: 13330 AN XY: 74414

African (AFR) AF: 0.120 AC: 4996 AN: 41542

American (AMR) AF: 0.203 AC: 3108 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 970 AN: 3468

East Asian (EAS) AF: 0.0238 AC: 123 AN: 5166

South Asian (SAS) AF: 0.0601 AC: 290 AN: 4828

European-Finnish (FIN) AF: 0.123 AC: 1309 AN: 10602

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

European-Non Finnish (NFE) AF: 0.246 AC: 16728 AN: 67996

Other (OTH) AF: 0.241 AC: 509 AN: 2110

Alfa AF: 0.231 Hom.: 16059

Bravo AF: 0.194

TwinsUK AF: 0.248 AC: 918

ALSPAC AF: 0.244 AC: 942

ESP6500AA AF: 0.124 AC: 545

ESP6500EA AF: 0.248 AC: 2127

ExAC AF: 0.182 AC: 22083

Asia WGS AF: 0.0560 AC: 196 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
-	-	3	Autosomal recessive distal spinal muscular atrophy 1 (3)
-	-	3	not specified (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	0.072
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	10
DANN	Benign	0.74
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.36	N
PhyloP100		1.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.16
Sift	Benign	0.74	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.048
MPC		0.17
ClinPred		0.0019	T
GERP RS		0.050
PromoterAI		-0.010	Neutral
Varity_R		0.076
gMVP		0.31
Mutation Taster		=92/8	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: rs10896380; hg19: chr11-68682402; COSMIC: COSV54823560; COSMIC: COSV54823560;