Genetic Variant NM_138272.3:c.62C>G (chr6-31723639-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_138272.3(MPIG6B):c.62C>G(p.Ala21Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,561,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

MPIG6B
NM_138272.3 missense, splice_region

Scores

Splicing: ADA: 0.001254

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.248

Publications

3 publications found

Variant links:

Genes affected

MPIG6B (HGNC:13937): (megakaryocyte and platelet inhibitory receptor G6b) This gene is a member of the immunoglobulin (Ig) superfamily and is located in the major histocompatibility complex (MHC) class III region. The protein encoded by this gene is a glycosylated, plasma membrane-bound cell surface receptor, but soluble isoforms encoded by some transcript variants have been found in the endoplasmic reticulum and Golgi before being secreted. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MPIG6B Gene-Disease associations (from GenCC):

thrombocytopenia, anemia, and myelofibrosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

MPIG6B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026452422).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138272.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MPIG6B	NM_138272.3	MANE Select	c.62C>G	p.Ala21Gly	missense splice_region	Exon 2 of 6	NP_612116.1	O95866-1
MPIG6B	NM_025260.4		c.62C>G	p.Ala21Gly	missense splice_region	Exon 2 of 6	NP_079536.2
MPIG6B	NM_138277.3		c.62C>G	p.Ala21Gly	missense splice_region	Exon 2 of 5	NP_612121.1	O95866-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MPIG6B	ENST00000649779.1	MANE Select	c.62C>G	p.Ala21Gly	missense splice_region	Exon 2 of 6	ENSP00000497720.1	O95866-1
MPIG6B	ENST00000375809.7	TSL:1	c.62C>G	p.Ala21Gly	missense splice_region	Exon 2 of 6	ENSP00000364967.3	O95866-2
MPIG6B	ENST00000375810.8	TSL:1	c.62C>G	p.Ala21Gly	missense splice_region	Exon 2 of 5	ENSP00000364968.4	O95866-7

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000230

AC:

AN:

208790

AF XY:

0.000212

show subpopulations

Gnomad AFR exome

AF:

0.000334

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000267

Gnomad OTH exome

AF:

0.000399

GnomAD4 exome

AF:

0.000235

AC:

331

AN:

1409164

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

142

AN XY:

696616

show subpopulations

African (AFR)

AF:

0.000593

AC:

AN:

32058

American (AMR)

AF:

0.000468

AC:

AN:

38440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23026

East Asian (EAS)

AF:

0.00

AC:

AN:

39280

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79702

European-Finnish (FIN)

AF:

0.0000440

AC:

AN:

45466

Middle Eastern (MID)

AF:

0.000183

AC:

AN:

5452

European-Non Finnish (NFE)

AF:

0.000254

AC:

276

AN:

1087590

Other (OTH)

AF:

0.000241

AC:

AN:

58150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000256

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41578

American (AMR)

AF:

0.000392

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000191

Hom.:

Bravo

AF:

0.000287

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000231

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Thrombocythemia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.024

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.84

M_CAP

Benign

0.014

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

0.25

PROVEAN

Benign

-2.1

REVEL

Benign

0.024

Sift

Benign

0.055

Sift4G

Benign

0.20

Polyphen

0.0090

Vest4

0.46

MVP

0.12

MPC

1.1

ClinPred

0.016

GERP RS

0.076

PromoterAI

0.0078

Neutral

(source)

Varity_R

0.15

gMVP

0.40

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0013

dbscSNV1_RF

Benign

0.33

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over