rs74641138

Positions:

chr12-56454295-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 14/19 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

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 links:

ENSG00000285528 (HGNC:):

ENSG00000285528 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Lens fiber major intrinsic protein (size 262) in uniprot entity MIP_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_012064.4

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 [Likely_benign]. Clinvar id is 260169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56454295-C-T is described in Lovd as [Likely_benign]. Variant chr12-56454295-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
MIP	NM_012064.4 link	c.319G>A	p.Val107Ile	missense_variant	1/4	ENST00000652304.1	NP_036196.1	P30301
MIP	XM_011538354.2 link	c.76-540G>A		intron_variant			XP_011536656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIP	ENST00000652304.1 link	c.319G>A	p.Val107Ile	missense_variant	1/4		NM_012064.4	ENSP00000498622.1		P30301
ENSG00000285528	ENST00000648304.1 link	n.183-540G>A		intron_variant				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

GnomAD3 exomes

AF:

0.0244

AC:

6119

AN:

250784

Hom.:

104

AF XY:

0.0251

AC XY:

3404

AN XY:

135800

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 SAS exome

AF:

0.0256

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

Gnomad4 AFR exome

AF:

0.00370

Gnomad4 AMR exome

AF:

0.00888

Gnomad4 ASJ exome

AF:

0.0255

Gnomad4 EAS exome

AF:

0.0552

Gnomad4 SAS exome

AF:

0.0252

Gnomad4 FIN exome

AF:

0.0431

Gnomad4 NFE exome

AF:

0.0272

Gnomad4 OTH exome

AF:

0.0256

GnomAD4 genome

AF:

0.0207

AC:

3158

AN:

152312

Hom.:

Cov.:

AF XY:

0.0221

AC XY:

1646

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00431

Gnomad4 AMR

AF:

0.0152

Gnomad4 ASJ

AF:

0.0262

Gnomad4 EAS

AF:

0.0382

Gnomad4 SAS

AF:

0.0269

Gnomad4 FIN

AF:

0.0456

Gnomad4 NFE

AF:

0.0258

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0243

Hom.:

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2019	This variant is associated with the following publications: (PMID: 21850180, 21647270, 19182255, 21921980, 20361015, 27456987, 24319327) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cataract 15 multiple types

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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

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

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

Varity_R

0.086

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over