chr11-118262458-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005797.4(MPZL2):c.416G>A(p.Arg139Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,614,018 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.00093 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 29 hom. )

Consequence

MPZL2
NM_005797.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.226

Publications

5 publications found

Variant links:

Genes affected

MPZL2 (HGNC:3496): (myelin protein zero like 2) Thymus development depends on a complex series of interactions between thymocytes and the stromal component of the organ. Epithelial V-like antigen (EVA) is expressed in thymus epithelium and strongly downregulated by thymocyte developmental progression. This gene is expressed in the thymus and in several epithelial structures early in embryogenesis. It is highly homologous to the myelin protein zero and, in thymus-derived epithelial cell lines, is poorly soluble in nonionic detergents, strongly suggesting an association to the cytoskeleton. Its capacity to mediate cell adhesion through a homophilic interaction and its selective regulation by T cell maturation might imply the participation of EVA in the earliest phases of thymus organogenesis. The protein bears a characteristic V-type domain and two potential N-glycosylation sites in the extracellular domain; a putative serine phosphorylation site for casein kinase 2 is also present in the cytoplasmic tail. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

MPZL2 Gene-Disease associations (from GenCC):

hearing loss, autosomal recessive 111
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: STRONG Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MPZL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007665932).

BP6

Variant 11-118262458-C-T is Benign according to our data. Variant chr11-118262458-C-T is described in ClinVar as Benign. ClinVar VariationId is 3033516.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000932 (142/152306) while in subpopulation EAS AF = 0.0235 (122/5182). AF 95% confidence interval is 0.0201. There are 2 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005797.4. 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
	MPZL2	NM_005797.4	MANE Select	c.416G>A	p.Arg139Gln	missense	Exon 3 of 6	NP_005788.1	O60487
	MPZL2	NM_144765.3		c.416G>A	p.Arg139Gln	missense	Exon 3 of 5	NP_658911.1	O60487

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MPZL2	ENST00000278937.7	TSL:1 MANE Select	c.416G>A	p.Arg139Gln	missense	Exon 3 of 6	ENSP00000278937.2	O60487
MPZL2	ENST00000438295.2	TSL:1	c.416G>A	p.Arg139Gln	missense	Exon 3 of 5	ENSP00000408362.2	O60487
MPZL2	ENST00000887115.1		c.416G>A	p.Arg139Gln	missense	Exon 3 of 6	ENSP00000557174.1

Frequencies

GnomAD3 genomes

AF:

0.000926

AC:

141

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0235

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00147

AC:

370

AN:

250932

AF XY:

0.00152

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0162

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00109

AC:

1598

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

818

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0294

AC:

1167

AN:

39700

South Asian (SAS)

AF:

0.00101

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00177

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.000104

AC:

116

AN:

1112002

Other (OTH)

AF:

0.00330

AC:

199

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

190

284

379

474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.000932

AC:

142

AN:

152306

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41568

American (AMR)

AF:

0.0000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0235

AC:

122

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.00114

Hom.:

Bravo

AF:

0.000933

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.00159

AC:

193

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

MPZL2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.094

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0077

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.88

PhyloP100

0.23

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.43

REVEL

Benign

0.070

Sift

Benign

0.29

Sift4G

Benign

0.39

Polyphen

0.010

Vest4

0.15

MVP

0.48

MPC

0.065

ClinPred

0.028

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.092

gMVP

0.50

Mutation Taster

=97/3

polymorphism

(source)

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

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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