11-68906199-G-C

Variant names:

• chr11-68906199-G-C
• rs376644749
• NM_002180.3:c.217G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002180.3(IGHMBP2):​c.217G>C​(p.Gly73Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12993509).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3	c.217G>C	p.Gly73Arg	missense_variant	Exon 2 of 15	ENST00000255078.8	NP_002171.2
IGHMBP2	XM_047426881.1	c.217G>C	p.Gly73Arg	missense_variant	Exon 2 of 15		XP_047282837.1
IGHMBP2	XM_017017671.3	c.217G>C	p.Gly73Arg	missense_variant	Exon 2 of 12		XP_016873160.1
IGHMBP2	XM_005273976.3	c.217G>C	p.Gly73Arg	missense_variant	Exon 2 of 9		XP_005274033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.217G>C	p.Gly73Arg	missense_variant	Exon 2 of 15	1	NM_002180.3	ENSP00000255078.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	7.7
DANN	Benign	0.67
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.77	T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N;D
REVEL	Benign	0.15
Sift	Benign	0.29	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.086	B;.
Vest4		0.22
MutPred		0.52		Gain of MoRF binding (P = 0.0512);Gain of MoRF binding (P = 0.0512);
MVP		0.83
MPC		0.28
ClinPred		0.11	T
GERP RS		1.7
Varity_R		0.12
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs376644749; hg19: chr11-68673667;