rs74641138

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012064.4(MIP):c.319G>A(p.Val107Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,614,060 control chromosomes in the GnomAD database, including 682 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 54 hom., cov: 32)

Exomes 𝑓: 0.027 ( 628 hom. )

Consequence

MIP
NM_012064.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.45

Publications

24 publications found

Variant links:

Genes affected

MIP (HGNC:7103): (major intrinsic protein of lens fiber) Major intrinsic protein is a member of the water-transporting aquaporins as well as the original member of the MIP family of channel proteins. The function of the fiber cell membrane protein encoded by this gene is undetermined, yet this protein is speculated to play a role in intracellular communication. The MIP protein is expressed in the ocular lens and is required for correct lens function. This gene has been mapped among aquaporins AQP2, AQP5, and AQP6, in a potential gene cluster at 12q13. [provided by RefSeq, Jul 2008]

MIP Gene-Disease associations (from GenCC):

cataract 15 multiple types
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
cerulean cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset lamellar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset posterior polar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset sutural cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MIP links:

ENSG00000285528 (HGNC:):

ENSG00000285528 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004590571).

BP6

Variant 12-56454295-C-T is Benign according to our data. Variant chr12-56454295-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIP	NM_012064.4 link	c.319G>A	p.Val107Ile	missense_variant	Exon 1 of 4	ENST00000652304.1	NP_036196.1	P30301
MIP	XM_011538354.2 link	c.76-540G>A		intron_variant	Intron 3 of 5		XP_011536656.1
MIP	XM_017019306.2 link	c.-384G>A		upstream_gene_variant			XP_016874795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIP	ENST00000652304.1 link	c.319G>A	p.Val107Ile	missense_variant	Exon 1 of 4		NM_012064.4	ENSP00000498622.1		P30301
ENSG00000285528	ENST00000648304.1 link	n.183-540G>A		intron_variant	Intron 1 of 3			ENSP00000497190.1		A0A3B3IS89

Frequencies

GnomAD3 genomes

AF:

0.0208

AC:

3163

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00432

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.0152

Gnomad ASJ

AF:

0.0262

Gnomad EAS

AF:

0.0385

Gnomad SAS

AF:

0.0275

Gnomad FIN

AF:

0.0456

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0258

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0244

AC:

6119

AN:

250784

AF XY:

0.0251

show subpopulations

Gnomad AFR exome

AF:

0.00356

Gnomad AMR exome

AF:

0.00839

Gnomad ASJ exome

AF:

0.0233

Gnomad EAS exome

AF:

0.0355

Gnomad FIN exome

AF:

0.0443

Gnomad NFE exome

AF:

0.0263

Gnomad OTH exome

AF:

0.0255

GnomAD4 exome

AF:

0.0272

AC:

39794

AN:

1461748

Hom.:

628

Cov.:

AF XY:

0.0273

AC XY:

19837

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.00370

AC:

124

AN:

33478

American (AMR)

AF:

0.00888

AC:

397

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0255

AC:

666

AN:

26132

East Asian (EAS)

AF:

0.0552

AC:

2193

AN:

39700

South Asian (SAS)

AF:

0.0252

AC:

2177

AN:

86256

European-Finnish (FIN)

AF:

0.0431

AC:

2300

AN:

53318

Middle Eastern (MID)

AF:

0.0262

AC:

151

AN:

5768

European-Non Finnish (NFE)

AF:

0.0272

AC:

30238

AN:

1111980

Other (OTH)

AF:

0.0256

AC:

1548

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

2175

4350

6525

8700

10875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1160

2320

3480

4640

5800

<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:

0.0207

AC:

3158

AN:

152312

Hom.:

Cov.:

AF XY:

0.0221

AC XY:

1646

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00431

AC:

179

AN:

41562

American (AMR)

AF:

0.0152

AC:

233

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

AN:

3472

East Asian (EAS)

AF:

0.0382

AC:

198

AN:

5182

South Asian (SAS)

AF:

0.0269

AC:

130

AN:

4828

European-Finnish (FIN)

AF:

0.0456

AC:

484

AN:

10618

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0258

AC:

1754

AN:

68022

Other (OTH)

AF:

0.0156

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

159

319

478

638

797

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0242

Hom.:

152

Bravo

AF:

0.0171

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0267

AC:

103

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0265

AC:

228

ExAC

AF:

0.0251

AC:

3044

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

EpiCase

AF:

0.0242

EpiControl

AF:

0.0245

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 12, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21850180, 21647270, 19182255, 21921980, 20361015, 27456987, 24319327) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cataract 15 multiple types

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.59

PhyloP100

1.4

PrimateAI

Benign

0.40

PROVEAN

Benign

0.020

REVEL

Benign

0.23

Sift

Benign

0.54

Sift4G

Benign

0.46

Polyphen

0.0080

Vest4

0.035

MPC

0.34

ClinPred

0.0017

GERP RS

4.3

PromoterAI

0.012

Neutral

(source)

Varity_R

0.086

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over